Abuse deterrent and anti-dose dumping pharmaceutical salts useful for the treatment of attention deficit/hyperactivity disorder

ABSTRACT

A pharmaceutical composition comprising a drug substance consisting essentially of a pharmaceutically acceptable organic acid addition salt of an amine containing pharmaceutically active compound wherein the amine containing pharmaceutical active compound is selected from the group consisting of racemic or single isomer ritalinic acid or phenethylamine derivatives and the drug substance has a physical form selected from amorphous and polymorphic.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of pending U.S. patentapplication Ser. No. 12/846,936 filed Jul. 30, 2010 which isincorporated herein by reference. This application is related to U.S.patent application Ser. Nos. 11/805,225 filed May 22, 2007; 11/973,252filed Oct. 5, 2007; 12/080,514 filed Apr. 3, 2008; 12/080,513 filed Apr.3, 2008; 12/080,531 filed Apr. 3, 2008; 11/595,379 filed Nov. 10, 2006now U.S. Pat. No. 7,718,649 issued May 18, 2010; 11/843,690 filed Aug.23, 2007; 11/928,592 filed Oct. 30, 2007; 11/932,336 filed Oct. 31,2007; 12/423,641 filed Apr. 14, 2009 and 12/537,664 filed Aug. 7, 2009each of which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

The present invention is related to pharmaceutical compositions whichare particularly suitable for treating Attention Deficit/HyperactivityDisorder (ADHD, also known as ADD, both terms may be usedinterchangeably herein). More particularly, the present invention isrelated to pharmaceutical compositions, particularly comprising racemicor single isomer ritalinic acid or phenethylamine derivatives, such asmethylphenidate or amphetamine, which can be rendered less susceptibleto abuse or dose dumping and which can be tailored to achieve specificlipophilic and hydrophilic properties.

Shire is a prominent pharmaceutical company engaged in marketingmedication for the treatment of Attention Deficit/Hyperactivity Disorder(ADHD). In a “Shire News” informational newsletter published on theinternet entitled, “Results from a European Caregiver Survey Highlightthe Impact of Attention Deficit Hyperactivity Disorder (ADHD) on theChild and the Family”, the following excerpt from the section “AboutADHD” is included below as a primer on ADHD. “ADHD is one of the mostcommon psychiatric disorders in children and adolescents. Worldwideprevalence of ADHD is estimated at 5.3 percent (with large variability),according to a comprehensive systematic review of this topic publishedin 2007 in the American Journal of Psychiatry. In the United States,approximately 7.8 percent of all school-aged children, or about 4.4million children aged 4 to 17 years, have been diagnosed with ADHD atsome point in their lives, according to the Centers for Disease Controland Prevention (CDC). The disorder is also estimated to affect 4.4percent of US adults aged 18 to 44 based on results from the NationalComorbidity Survey Replication. When this percentage is extrapolated tothe full US population aged 18 and over, approximately 9.8 millionadults are believed to have ADHD. ADHD is a psychiatric behavioraldisorder that manifests as a persistent pattern of inattention and/orhyperactivity-impulsivity that is more frequent and severe than istypically observed in individuals at a comparable level of development.The specific etiology of ADHD is unknown and there is no singlediagnostic test for this syndrome. Adequate diagnosis requires the useof medical and special psychological, educational and social resources,utilizing diagnostic criteria such as Diagnostic and Statistical Manualof Mental Disorders-IV (DSM-IV-TR) or International Classification ofDiseases 10 (ICD-10). Although there is no “cure” for ADHD, there areaccepted treatments that specifically target its symptoms. Standardtreatments include educational approaches, psychological, or behavioralmodification, and medication.”

The treatment of ADHD as manifested in adults and children is a diseasewith known treatment regimens. An overview of the symptoms, signs,diagnosis, prognosis, treatment and therapeutic agents applicable tothese learning and developmental disorders can be found in The MerckManual 18^(th) Edition, ©2006, published by Merck Research Laboratories,pp. 2483-2486. Two drugs are principally used to treat these conditions:methylphenidate and dextro-amphetamine. The dosing regimen generallyconsists of first titrating the patient with immediate release (IR)dosage forms to effect the desired change while minimizing adverseeffects followed by switching to an extended release (ER) formulationonce the patient's response to the drug is understood. Bothdextro-amphetamine and methylphenidate, in either IR or ER formulations,are stimulants and prone to abuse, misuse and diversion.

The abuse, misuse and diversion of controlled substances is discussed atlength in U.S. patent application Ser. Nos. 11/805,225 [Bristol et al.],and 11/973,252 [King, et al.] and 12/423,641 [King et al.] whereinincluded are technical approaches to imparting anti-abuse and abusedeterrent features to controlled substances. The abuse ofdextro-amphetamine and methylphenidate, both of which are controlledsubstances, is widespread. These drugs are readily prescribed andconsequently, their common availability or access by diversion has madethem comparatively easy targets for those people intent on abuse ormisuse of the drug. The challenge to the pharmaceutical industry and tomedical professionals is to provide these medications to patients ingenuine need of the drug's therapeutic benefits while restricting oreliminating the ability to abuse the drug.

In the case of dextro-amphetamine, New River Pharmaceuticals has risento the abuse deterrent/misuse/diversion challenge by preparing a prodrugform of dextro-amphetamine. New River's U.S. Pat. No. 7,105,486 B2(Mickle et al.), the disclosure of which is incorporated herein byreference, describes the covalent attachment of L-lysine to the drugsubstance, amphetamine, to provide compounds and compositions exhibitingabuse-resistant properties and which are useful for the treatment ofdisorders including attention deficit hyperactivity disorder (ADHD),attention deficit disorder (ADD), narcolepsy and obesity. The drugproduct incorporating the prodrug delivers an abuse deterrent featurethrough chemical means which would require some expertise to defeat—andonly through chemical transformation. Unfortunately, the prodrugapproach, in general, requires significant R&D resources to tailor eachprodrug to a host of regulatory specifications before market approvalcan be granted by the FDA. Consequently, the prodrug approach is costly,time-intensive and does not provide a universal, platform solution toimparting abuse deterrent properties to the medically necessaryamine-containing controlled substances. The invention described hereinencompasses a platform approach to imparting abuse deterrent propertiesat the molecular level through unique salt forms of the opioidalkaloids.

Not surprisingly, the abuse, misuse and diversion of(dextro)-amphetamine and methylphenidate (racemic and single isomer) isdue to the psychoactive effect these drugs exhibit which is similar tococaine. In “The Chemistry of Mind-Altering Drugs, History,Pharmacology, and Cultural Context”, by Daniel M. Perrine, ©1996,published by the American Chemical Society, p. 196-198, the authorsreport on a study conclusively demonstrating methylphenidate and cocaineacted on the same part of the brain. Similarly, on page 193 the authorsreport that the final psychotic toxicity of amphetamines is “essentiallyidentical to that found with cocaine”. While these drugs providenecessary medical treatment, their abuse serves no valued purpose tosociety. Consequently, the challenge is to provide these drugs, as drugsubstances and in dosage forms (drug products) which are not easilyabused or misused and thereby diminish the motive for diversion.

In addition to the scientific and technical challenges faced by drugsubstance and product manufacturers, the United States governmentrecognizes the severe detrimental consequences drug abuse has on theNation and has taken action, principally through the Food and DrugAdministration (FDA), in an effort to mitigate drug abuse. A summary ofthe FDA's intent, philosophy and actions is found in the FederalRegister, Volume 74, Number 74, Monday Apr. 20, 2009, pages 17967-17970as it relates to their Risk Evaluation and Mitigation Strategies (REMS)program for opioid-based drug products. However, a REMS programrequirement may be required by all drug product manufacturers toascertain the risk/benefit to (controversial) drug products asauthorized by the Food and Drug Administration Amendments Act of 2007.Beyond cited opioids in the FDA's Federal Registry entry, all controlledsubstances including those of the present invention will likely besubject to a REMS requirement. A top level overview of the REMSinitiative, presented by the FDA's top administrators, is availableon-line. As the effort to fight drug abuse increases, the terminologyemployed to address the topic is evolving. In previous applications bythe present inventors, “anti-abuse” was employed as a term to describeproperties imparted to drug substances and drug products as a result ofdesign engineering to these substances and products, features whichinhibit their use in a manner for which they were not intended. As theterminology has evolved within administrative law, the term“abuse-deterrent” is more often employed. Within the context of thisdisclosure, no limitation is implied through the use of either term andboth are engendered to be interpreted in the broadest sense. However,for completeness and to provide a broader understanding of the inventionherein, the United States Food and Drug Administration in their January2010 issuance of Guidance for Industry: Assessment of Abuse Potential ofDrugs, it is stated: “Currently, the concept of abuse deterrence isviewed as the introduction of some limits or impediments to abuse, asopposed to the outright elimination of abuse.”

The Government Accounting Office (GAO) in a publication entitled,“Prescription Drugs, OxyContin Abuse and Diversion and Efforts toAddress the Problem”, (GAO-04-110) in the “Recommendation for ExecutiveAction”, page 42, stated: “To improve efforts to prevent or identify theabuse and diversion of schedule II controlled substances, we recommendthat the Commissioner of Food and Drugs ensure that FDA's riskmanagement plan guidance encourages pharmaceutical manufacturers thatsubmit new drug applications for these substances to include plans thatcontain a strategy for monitoring the use of these drugs and identifyingpotential abuse and diversion problems.” It is well known that theamphetamines and methylphenidate are intentionally abused and divertedfor illicit purpose.

Clearly there remains a need to address the abuse, misuse and diversionof schedule II controlled substances (both the active pharmaceuticalingredient and for the formulated dosage product). A host of technicalrequirements must be met in addition to the regulatory administrativerequirements to meet society's needs. Beyond technical requirements,today's pharmaceutical marketplace requires inventions be consistentwith the prevailing politics and policy of the federal government. Theadministrative controls being placed on the stakeholders involved in thecommercial use of controlled substances are burdensome. The stakeholdersinclude the drug manufacturer, distributor, the prescriber (physicianand other medical personnel), dispenser (pharmacist) and the patient.Such burdensome administrative controls such as health providercertifications and the like may have the unintentional outcome ofrestricting necessary medications to those patients legitimately in needof the controlled substance, such as those substances of the presentinvention.

There has been a long felt need for pharmaceuticals, pharmaceuticalsystems, and methods of predictably altering pharmaceuticals to achievethe goals set forth above. Pharmaceuticals, pharmaceutical systems, andmethods of predictably altering pharmaceuticals which are lesssusceptible to abuse, and particularly dose dumping, are providedherein. It is an object of the invention is to provide a beneficialtechnical solution which does not overwhelm the healthcare system andaddresses an entire product/therapeutic family to curb prescriber anddispenser confusion.

SUMMARY OF THE INVENTION

It is an object of the invention is to provide a beneficial technicalsolution to drug abuse which does not overwhelm the healthcare systemand which addresses an entire product/therapeutic family to curbprescriber and dispenser confusion.

It is an object of the invention to provide organic acid addition saltsof racemic and single-isomer methylphenidate and amphetamine exhibitingabuse deterrent properties including anti-dose dumping characteristics.

A particular advantage of the invention is the ability to establish apatient's therapeutic treatment for ADD/ADHD with immediate releasedosage products and then exchanging the patient's treatment to a dosageformulation exhibiting abuse deterrent properties.

A particular advantage of the present invention is the ability toprovide medical professionals, or prescribers, the ability to prescribean abuse deterrent formulation for the therapeutic treatment of patientswith a propensity toward drug abuse.

One embodiment of the present invention is to provide a means forfulfilling a United States Food and Drug Administration mandate to allstakeholders in the manufacture, prescribing, dispensing and to therecipient patient to curb drug abuse and to demonstrate compliance withthe FDA's statutorily driven REMS program.

An embodiment of the present invention is the ability to provide abusiness franchise or enterprise solution for the manufacture,distribution, prescription and fulfillment of medically necessary drugproducts of a given therapeutic category and which exhibit abusedeterrent properties.

An advantage of the invention is the ability to provide afranchise/enterprise regulatory compliant business solution for theprovision of amine-containing controlled substances while fulfilling amedical need exhibiting abuse deterrent properties.

An advantage of the present invention is the ability to provide drugsubstances within a therapeutic family of drug products which exhibitabuse deterrent properties.

It is a feature of the present invention to provide methylphenidateorganic acid addition salts and amphetamine organic acid addition saltspossessing abuse-deterrent properties which are useful for the treatmentof ADD or ADHD.

It is an object of the present invention to employ abuse deterrenttechnology to drug substances which are currently unapproved yet whichcould be rendered sufficiently safe that they could serve a legitimatemedical need.

It is an object of the present invention to provide the organic acidaddition salt of cocaine exhibiting abuse deterrent features and usefulfor the treatment of ADHD.

It is an object of the present invention to provide organic acidaddition salts of amine containing compounds wherein brain receptorselectivity is unaltered by the abuse deterrent feature.

It is yet another object of the present invention to provide an organicacid moiety which, when reacted with an amine, provides a non-toxic,drug delivery system. Furthermore, the organic acid moiety is, bydesign, engineering and through chemical derivatization adjusted topredictably alter its hydrophilic or lipophilic balance to aid as a drugdelivery system.

A particular advantage of the present invention is that the organic acidmoiety can be chemically derivatized, by reaction with an amine, toalter the hydrophilic or lipophilic balance of the resulting organicacid addition salt.

Another advantage of the present invention is that the organic acidmoiety can be chemically modified to selectively impart a desireddissolution performance feature of salts formed between the organic acidmoiety and amine-containing active pharmaceutical ingredients.

In yet another advantage of the present invention the organic acidmoiety can be selected to enhance or increase the lipophilicity of anamine-containing active pharmaceutical ingredient upon salt formationwith the organic acid moiety, wherein the moiety contains hydrophobicsubstitution.

It is another object of the invention to enhance or increase thehydrophilicity of an amine-containing active pharmaceutical ingredientupon salt formation with an organic acid moiety, the moiety containinghydrophilic substitution.

It is another object of the invention to increase the resistance of anamine-containing organic acid addition salt to dissolution in low pHenvironments, particularly in the human gastrointestinal tract.

It is another object of the present invention to provide controlledrelease of the amine-containing active pharmaceutical ingredient fromits organic acid addition salt by selection of the organic acidcomponent wherein the hydrophilic-lipophilic balance of the salt and itsresponse to pH have been altered by chemical design of the organic acidcomponent.

The present invention includes modifications to the ortho-hydroxyorganic acid components of the invention to increase its hydrophilicityand that of subsequent salts formed by reaction with amine-containingactive pharmaceutical ingredients. Such modifications include but arenot limited to attaching polar, hydrophilic groups to the organic acidmoiety. Particularly preferred polar groups are selected from the groupconsisting of ethers, esters, alcohols, oligomeric ethers derived fromalkylene oxides, polyoxyalkylenes, and the like.

The present invention includes modifications to the ortho-hydroxyorganic acids to increase the lipophilicity and that of subsequent saltsformed by reaction with amine-containing active pharmaceuticalingredients. Such modifications include but are not limited to attachingnon-polar, lipophilic groups to the organic acid moiety. Particularlypreferred non-polar groups are selected from the group consisting oflinear and branched alkyl, aryl, alkyl/aryl groups and the like.

A particular feature of the present invention is the ability to provideorganic acid derivatives incorporating a surfactant moiety as adissolution profile modifier which are capable of forming salts withamine-containing active pharmaceutical compounds.

Yet another aspect of the invention is to chemically attach to theorganic acid component a substituent possessing surfactant exhibitinganionic, cationic and neutral surfactant properties.

Yet another object of the present invention is the ability to providecontrolled release of an amine-containing active pharmaceuticalingredient from its organic acid addition salt. This is accomplished byselection of the organic acid component wherein thehydrophilic-lipophilic balance of the salt, its response to pH, and itsdissolution properties imparted through the dissolution profile modifierof the organic acid component have been altered by design.

A particular feature of the present invention is the ability tooptimize, adjust or otherwise tune the dissolution properties of organicacid addition salts of amine containing active pharmaceuticalingredients by selection of properties of the salt and the organic acidcomponent as a delivery mechanism utilizing: the selection of: a) theorganic acid family, b) the stoichiometry available in salt formationsuch as 2:1 or 1:1, c) the amorphous or polymorphic form of the salt andd) substitution upon the organic acid component to adjust its: 1)hydrophilic-lipophilic balance, 2) sensitivity to pH, and 3) surfactantproperties. Each of these factors allows for the design and engineeringof dissolution properties of amine-containing active pharmaceuticalingredients.

A feature of the present invention is the ability to optimize an invitro and in vivo dissolution profile of an amine-containing activepharmaceutical ingredients at the molecular level by:

a) preparation of its bis-functional acid salt;

b) selection of a preferred stoichiometric ratio of the bis-functionalacid salt intermediate compared to amine-containing activepharmaceutical ingredient and to amine-containing hydrophilic (orconversely, lipophilic) components used to form the salt;

c) evaluation and optimization of the stoichiometry ratio to optionallyproduce an amorphous or polymorphic salt;

d) evaluation and optimization of the stoichiometry ratio to produce thepreferred dissolution profile; based on a) through c) above; and

e) an iterative evaluation and optimization of the hydrophilic (orlipophilic) component to identify a preferred molecular weight range toyield the desired dissolution profile.

An aspect of the present invention is the preparation of abis-functional salt wherein at least one functionality portion of thesalt is used to deliver a physiologically active and/or psychoactivealkaloid and/or amine-containing active pharmaceutical ingredient;another functionality of the salt is to provide the delivery mechanismof the alkaloid and/or active pharmaceutical ingredient.

It is yet another aspect of the invention to provide a processmethodology suitable for preparing a mixed organic acid addition salt ofamine-containing active pharmaceutical ingredients and an essentiallyinactive amine component, the mixed organic acid addition salt arisingfrom the stoichiometric displacement of one essentially inactive aminecomponent of a bis-substituted organic acid.

It is another object of the present invention to employ xinafoate saltsof amine containing active pharmaceutical ingredients in formulated drugproducts in order to deliver the active pharmaceutical ingredient to theintestinal tract by retarding the rate of release in the stomach andenhance the stability of low pH sensitive drugs. In addition, acombination of pamoate and xinafoate salts of a given amine containingcontrolled substance would provide for a tunable and targeted releaseprofile in a dosage form.

These and other features of the invention are provided in apharmaceutical composition comprising a drug substance consistingessentially of a pharmaceutically acceptable organic acid addition saltof an amine containing pharmaceutically active compound wherein theamine containing pharmaceutical active compound is selected from thegroup consisting of racemic or single isomer ritalinic acid orphenethylamine derivatives, particularly methylphenidate andamphetamine, and the drug substance has a physical form selected fromamorphous and polymorphic.

Yet another embodiment is provided in a pharmaceutical compositioncomprising a drug substance consisting essentially of A-B-C wherein A isan amine containing pharmaceutically active compound; C is an aminewhich can be the same as A, and B is a bidentate linking group used toionically or covalently link A and C, and defined by the formula:

wherein Y¹ and Y² are independently selected from nitrogen, oxygen andsulfur;G¹ and G² independently represent ionically or covalently bound groups;R¹⁹ and R¹¹ are present when necessary to satisfy the valence of Y¹ andY², respectively, and are independently selected from hydrogen and analkyl of 1-6 carbons; aryl of 6-12 carbons, alkylacyl of 1-8 carbons orarylacyl 7-15 carbons;R¹² and R¹³ are independently selected from hydrogen, alkyl or 1-6carbons, alkylacyl of 1-8 carbons or arylacyl of 7-15 carbons;R¹⁴ will replace one of R¹⁵, R¹⁶, R¹⁷ or R¹⁸ and one of R¹⁹, R²⁰, R²¹ orR²² and is an alkyl or branched alkyl of 1-10 carbons, aryl, arylalkylof 7-15 carbons and wherein R¹⁴ may include at least one opticallyactive carbon; andR¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹ and R²², are independently selectedfrom hydrogen, alkyl of 1-6 carbons, and wherein adjacent groups may betaken together to form a cyclic alkyl or cyclic aryl moiety

Yet another embodiment is provided in a drug substance consistingessentially of a pharmaceutically acceptable organic acid addition saltof an amine containing pharmaceutically active compound wherein theamine containing pharmaceutical active compound is selected from thegroup consisting of racemic or single isomer ritalinic acid orphenethylamine derivatives, particularly methylphenidate andamphetamine, and the drug substance has a physical form selected fromamorphous and polymorphic and wherein the drug substance is useful forthe treatment of a therapeutic ailment administration and the drugsubstance exhibits anti-abuse properties when employed innon-therapeutic administration.

Yet another embodiment is provided in a drug substance consistingessentially of A-B-C wherein A is a pharmaceutically active compound; Cis a dissolution modifying amine and B is a bidentate linking group usedto ionically or covalently link A and C, and defined by the formula:

wherein Y¹ and Y² are independently selected from nitrogen, oxygen andsulfur;G¹ and G² independently represent ionically or covalently bound groups;R¹⁰ and R¹¹ are present when necessary to satisfy the valence of Y¹ andY², respectively, and are independently selected from hydrogen and analkyl of 1-6 carbons; aryl of 6-12 carbons, alkylacyl of 1-8 carbons orarylacyl 7-15 carbons;R¹² and R¹³ are independently selected from hydrogen, alkyl or 1-6carbons, alkylacyl of 1-8 carbons or arylacyl of 7-15 carbons;R¹⁴ will replace one of R¹⁵, R¹⁶, R¹⁷ or R¹⁸ and one of R¹⁹, R²⁰, R²¹ orR²² and is an alkyl or branched alkyl of 1-10 carbons, aryl, arylalkylof 7-15 carbons and wherein R¹⁴ may include at least one opticallyactive carbon; andR¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹ and R²², are independently selectedfrom hydrogen, alkyl of 1-6 carbons, and wherein adjacent groups may betaken together to form a cyclic alkyl or cyclic aryl moiety; andwherein said drug substance is useful for the treatment of a therapeuticailment administration and exhibits anti-abuse properties when employedin non-therapeutic administration.

Yet another embodiment is provided in a method for mitigating dosedumping comprising:

providing a drug product comprising a pharmaceutically acceptableorganic acid addition salt of an amine containing pharmaceuticallyactive compound wherein the amine containing pharmaceutically activecompound is selected from the group consisting of racemic or singleisomer ritalinic acid or phenethylamine derivatives, particularlymethylphenidate and amphetamine, and the drug substance has a physicalform selected from amorphous and polymorphic wherein the drug substancemeets at least one condition in 0.1 N HCl selected from the groupconsisting of: no more than 35% of the pharmaceutically active compoundis released at 30 minutes with 5 wt % ethanol in 0.1 N HCl;the percentage of pharmaceutically active compound released with atleast 5 wt % ethanol in 0.1 N HCl is no more than a percentage of activepharmaceutically active compound released in said 0.1 N HCl withoutethanol; and the percentage of drug substance released with 40 wt %ethanol in 0.1 N HCl does not exceed 60% while the percentage ofpharmaceutically active compound released under the conditions selectedfrom water, 0.1 N HCl, 5 wt % ethanol in 0.1 N HCl and 20 wt % ethanolin 0.1 N HCl does not exceed the pharmaceutically active compoundreleased with 40 wt % ethanol in 0.1 N HCl. It is particularly preferredthat no more than about 35% of the active pharmaceutical be releasedover an extended time, such as at least 45 minutes.

Yet another embodiment is provided in a drug product not susceptible todose dumping wherein the drug product comprises a drug substance whereinthe drug substance is a pharmaceutically acceptable organic acid salt ofan amine containing pharmaceutically active compound selected from thegroup consisting of racemic or single isomer ritalinic acid orphenethylamine derivatives, particularly, methylphenidate andamphetamine, and said drug substance meets at least one condition in 0.1N HCl selected from the group consisting of: no more than 35% of thedrug substance is released at 30 minutes with 5 wt % ethanol in said 0.1N HCl; the percentage of drug substance released with at least 5 wt %ethanol in said 0.1 N HCl is no more than a percentage of drug substancereleased in said 0.1 N HCl without ethanol; and the percentage of drugsubstance released with 40 wt % ethanol in 0.1 N HCl does not exceed 60%while the percentage of drug substance released under the conditionsselected from water, 0.1 N HCl, 5 wt % ethanol in 0.1 N HCl and 20 wt %ethanol in 0.1 N HCl does not exceed the drug substance released with 40wt % ethanol in 0.1 N HCl. It is particularly preferred that no morethan about 35% of the active pharmaceutical be released over an extendedtime, such as at least 45 minutes.

Yet another embodiment is provided in a method for mitigating dosedumping comprising:

providing a drug product comprising a drug substance consistingessentially of A-B-C wherein A is d-methylphenidate; C is an amine and Bis a bidentate linking group used to ionically or covalently link A andC, and defined by the formula:

wherein Y¹ and Y² are independently selected from nitrogen, oxygen andsulfur;G¹ and G² independently represent ionically or covalently bound groups;R¹⁰ and R¹¹ are present when necessary to satisfy the valence of Y¹ andY², respectively, and are independently selected from hydrogen and analkyl of 1-6 carbons; aryl of 6-12 carbons, alkylacyl of 1-8 carbons orarylacyl 7-15 carbons;R¹² and R¹³ are independently selected from hydrogen, alkyl or 1-6carbons, alkylacyl of 1-8 carbons or arylacyl of 7-15 carbons;R¹⁴ will replace one of R¹⁵, R¹⁶, R¹⁷ or R¹⁸ and one of R¹⁹, R²⁰, R²¹ orR²² and is an alkyl or branched alkyl of 1-10 carbons, aryl, arylalkylof 7-15 carbons and wherein R¹⁴ may include at least one opticallyactive carbon; andR¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹ and R²², are independently selectedfrom hydrogen, alkyl of 1-6 carbons, and wherein adjacent groups may betaken together to form a cyclic alkyl or cyclic aryl moiety; and whereinsaid drug substance meets at least one condition in 0.1 N HCl selectedfrom the group consisting of: no more than 35% of drug substance isreleased at 30 minutes with 5 wt % ethanol in 0.1 N HCl; the percentageof drug substance with at least 5 wt % ethanol in 0.1 N HCl is no morethan a percentage of drug substance in 0.1 N HCl without ethanol; andthe percentage of drug substance released with 40 wt % ethanol in 0.1 NHCl does not exceed 60% while the percentage of drug substance releasedunder the conditions selected from water, 0.1 N HCl, 5 wt % ethanol in0.1 N HCl and 20 wt % ethanol in 0.1 N HCl does not exceed the drugsubstance released with 40 wt % ethanol in 0.1 N HCl.

Yet another embodiment is provided in a drug product not susceptible todose dumping wherein the drug product comprises a drug substanceconsisting essentially of A-B-C wherein A is d-methylphenidate; C is anamine and B is a bidentate linking group used to ionically or covalentlylink A and C, and defined by the formula:

wherein Y¹ and Y² are independently selected from nitrogen, oxygen andsulfur;G¹ and G² independently represent ionically or covalently bound groups;R¹⁰ and R¹¹ are present when necessary to satisfy the valence of Y¹ andY², respectively, and are independently selected from hydrogen and analkyl of 1-6 carbons; aryl of 6-12 carbons, alkylacyl of 1-8 carbons orarylacyl 7-15 carbons;R¹² and R¹³ are independently selected from hydrogen, alkyl or 1-6carbons, alkylacyl of 1-8 carbons or arylacyl of 7-15 carbons;R¹⁴ will replace one of R¹⁵, R¹⁶, R¹⁷ or R¹⁸ and one of R¹⁹, R²⁰, R²¹ orR²² and is an alkyl or branched alkyl of 1-10 carbons, aryl, arylalkylof 7-15 carbons and wherein R¹⁴ may include at least one opticallyactive carbon; andR¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹ and R²², are independently selectedfrom hydrogen, alkyl of 1-6 carbons, and wherein adjacent groups may betaken together to form a cyclic alkyl or cyclic aryl moiety; and saiddrug substance meets at least one condition in 0.1 N HCl selected fromthe group consisting of no more than 35% of the drug substance isreleased at 30 minutes with 5 wt % ethanol in 0.1 N HCl; the percentageof drug substance with at least 5 wt % ethanol in said 0.1 N HCl is nomore than a percentage of drug substance released in said 0.1 N HClwithout ethanol; and the percentage of drug substance released with 40wt % ethanol in 0.1 N HCl does not exceed 60% while the percentage ofdrug substance released under the conditions selected from water, 0.1 NHCl, 5 wt % ethanol in 0.1 N HCl and 20 wt % ethanol in 0.1 N HCl doesnot exceed the drug substance released with 40 wt % ethanol in 0.1 NHCl.

Yet another embodiment is provided in a method for forming a drugsubstance consisting essentially of A-B-C wherein A is apharmaceutically active compound; C is an amine and B is a bidentatelinking group used to ionically or covalently link A and C, andcomprising:

mixing at least two moles of said pharmaceutically active compound orsaid amine with a mole of said bidentate linking group defined by theformula:

wherein Y³ and Y⁴ are independently selected from groups capable ofbeing displaced by at least one of said pharmaceutically active compoundand said amine;R¹¹² and R¹¹³ are independently selected from hydrogen, alkyl of 1-6carbons, alkylacyl of 1-8 carbons or arylacyl of 7-15 carbons;R¹¹⁴ will replace one of R¹¹⁵, R¹¹⁶, R¹¹⁷ or R¹¹⁸ and one of R¹¹⁹, R¹²⁰,R¹²¹ or R¹²² and is an alkyl or branched alkyl of 1-10 carbons, aryl,arylalkyl of 7-15 carbons and whereinR¹¹⁴ may include at least one optically active carbon; andR¹¹⁵, R¹¹⁶, R¹¹⁷, R¹¹⁸, R¹¹⁹, R¹²⁰, R¹²¹ and R¹²², are independentlyselected from hydrogen, alkyl of 1-6 carbons, and wherein adjacentgroups may be taken together to form a cyclic alkyl or cyclic arylmoiety; thereby forming a conjugate; andmixing 0.9 to 1.1 moles of other amine or said pharmaceutically activecompound with the conjugate thereby forming A-B-C.

Yet another embodiment is provided in a method for forming a drugsubstance consisting essentially of A-B-C wherein A is apharmaceutically active compound; C is an amine and B is a bidentatelinking group used to ionically or covalently link A and C, and definedby the formula:

-   -   wherein Y¹ and Y² are independently selected from nitrogen,        oxygen and sulfur;    -   G¹ and G² independently represent ionically or covalently bound        groups;    -   R¹⁰ and R¹¹ are present when necessary to satisfy the valence of        Y¹ and Y², respectively, and are independently selected from        hydrogen and an alkyl of 1-6 carbons; aryl of 6-12 carbons,        alkylacyl of 1-8 carbons or arylacyl 7-15 carbons; alkali earth        metals, ammonium, alkyl ammonium with 1-20 carbons and esters        with 1-20 carbons;    -   R¹² and R¹³ are independently selected from hydrogen, alkyl or        1-6 carbons, alkylacyl of 1-8 carbons or arylacyl of 7-15        carbons;    -   R¹⁴ will replace one of R¹⁵, R¹⁶, R¹⁷ or R¹⁸ and one of R¹⁹,        R²⁰, R²¹ or R²² and is an alkyl or branched alkyl of 1-10        carbons, aryl, arylalkyl of 7-15 carbons and wherein R¹⁴ may        include at least one optically active carbon; and    -   R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹ and R²², are independently        selected from hydrogen, alkyl of 1-6 carbons, and wherein        adjacent groups may be taken together to form a cyclic alkyl or        cyclic aryl moiety; comprising:    -   mixing at least 0.9 moles and no more than 1.1 moles of one of        said pharmaceutically active compound or said amine with a mole        of a bidentate linking group defined by

-   -   wherein Y³ and Y⁴ are independently selected from groups with        capable of being displaced by at least one of said        pharmaceutically active compound and said amine;    -   R¹¹² and R¹¹³ are independently selected from hydrogen, alkyl or        1-6 carbons, alkylacyl of 1-8 carbons or arylacyl of 7-15        carbons;    -   R¹¹⁴ will replace one of R¹¹⁵, R¹¹⁶, R¹¹⁷ or R¹¹⁸ and one of        R¹¹⁹, R¹²⁰, R¹²¹ or R¹²² and is an alkyl or branched alkyl of        1-10 carbons, aryl, arylalkyl of 7-15 carbons and wherein R¹¹⁴        may include at least one optically active carbon; and    -   R¹¹⁵, R¹¹⁶, R¹¹⁷, R¹¹⁸, R¹¹⁹, R¹²⁰, R¹²¹ and R¹²², are        independently selected from hydrogen, alkyl of 1-6 carbons, and        wherein adjacent groups may be taken together to form a cyclic        alkyl or cyclic aryl moiety;    -   thereby forming a conjugate; and    -   mixing at least 0.9 moles and no more than 1.1 moles of other of        said amine or said pharmaceutically active compound with a mole        of said conjugate thereby forming said A-B-C.

Yet another embodiment is provided in a pharmaceutical compositioncomprising:

a first drug substance consisting essentially of a pharmaceuticallyacceptable organic acid addition salt of a first amine containingpharmaceutically active compound wherein the first amine containingpharmaceutical active compound is selected from the group consisting ofracemic or single isomer ritalinic acid or phenethylamine derivatives,particularly methylphenidate and amphetamine, and the drug substance hasa physical form selected from amorphous and polymorphic with a firstpercent dissolution at a pH of 1 at 60 minutes at ambient temperature;anda second drug substance consisting essentially of a salt of a secondamine containing pharmaceutically active compound with a second percentdissolution at a pH of 1 at 60 minutes at ambient temperature.

Yet another embodiment is provided in a pharmaceutical compositioncomprising:

a first drug substance consisting essentially of a firstpharmaceutically acceptable organic acid addition salt of a first aminecontaining pharmaceutically active compound; and

a second drug substance consisting essentially of A-B-C wherein A is asecond pharmaceutically active compound, C is an amine and B used toionically or covalently link A and C, and is defined by the followingstructure:

wherein Y¹ and Y² are independently selected from nitrogen, oxygen andsulfur;G¹ and G² independently represent ionically or covalently bound groups;R¹⁰ and R¹¹ are present when necessary to satisfy the valence of Y¹ andY², respectively, and are independently selected from hydrogen and analkyl of 1-6 carbons; aryl of 6-12 carbons, alkylacyl of 1-8 carbons orarylacyl 7-15 carbons;R¹² and R¹³ are independently selected from hydrogen, alkyl or 1-6carbons, alkylacyl of 1-8 carbons or arylacyl of 7-15 carbons;R¹⁴ will replace one of R¹⁵, R¹⁶, R¹⁷ or R¹⁸ and one of R¹⁹, R²⁰, R²¹ orR²² and is an alkyl or branched alkyl of 1-10 carbons, aryl, arylalkylof 7-15 carbons and wherein R¹⁴ may include at least one opticallyactive carbon; andR¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹ and R²², are independently selectedfrom hydrogen, alkyl of 1-6 carbons, and wherein adjacent groups may betaken together to form a cyclic alkyl or cyclic aryl moiety.

Yet another embodiment is provided in a method for treating AttentionDeficit/Hyperactivity Disorder comprising the steps of:

determining a suitable dosage of a drug substance for a patient and adrug substance release profile;

providing at least one drug product comprising said suitable dosage ofsaid drug substance and said drug substance release profile wherein saiddrug substance is selected from the group consisting of:

a pharmaceutically acceptable organic acid addition salt of a firstamine containing pharmaceutically active compound wherein said firstamine containing pharmaceutical active compound is selected from thegroup consisting of racemic or single isomer ritalinic acid orphenethylamine derivatives, particularly methylphenidate andamphetamine, and said drug substance has a physical form selected fromamorphous and polymorphic; andA-B-C wherein A is a second amine containing pharmaceutically activecompound; C is an amine and B is a bidentate linking group used toionically or covalently link A and C, and is defined by the formula:

wherein Y¹ and Y² are independently selected from nitrogen, oxygen andsulfur;G¹ and G² independently represent ionically or covalently bound groups;R¹⁰ and R¹¹ are present when necessary to satisfy the valence of Y¹ andY², respectively, and are independently selected from hydrogen and analkyl of 1-6 carbons; aryl of 6-12 carbons, alkylacyl of 1-8 carbons orarylacyl 7-15 carbons;R¹² and R¹³ are independently selected from hydrogen, alkyl or 1-6carbons, alkylacyl of 1-8 carbons or arylacyl of 7-15 carbons;R¹⁴ will replace one of R¹⁵, R¹⁶, R¹⁷ or R¹⁸ and one of R¹⁹, R²⁰, R²¹ orR²² and is an alkyl or branched alkyl of 1-10 carbons, aryl, arylalkylof 7-15 carbons and wherein R¹⁴ may include at least one opticallyactive carbon; andR¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹ and R²², are independently selectedfrom hydrogen, alkyl of 1-6 carbons, and wherein adjacent groups may betaken together to form a cyclic alkyl or cyclic aryl moiety;medicating said patient with said drug substance thereby providing amedicated patient; determining a degree of physiological/psychologicaldisorder for said medicated patient; andproviding at least one second drug product comprising a second suitabledosage and a second drug release profile wherein said drug productcomprises said at least one drug substance.

Yet another embodiment is provided in a method of administering anactive pharmaceutical comprising:

providing a drug product comprising a drug substance in a dose suitablefor achieving a therapeutic dose of drug substance in a predeterminedtime wherein the therapeutic dose is not exceeded by ingestion ofalcohol at biological pH and the drug substance is selected from thegroup consisting of:a pharmaceutically acceptable organic acid addition salt of a firstamine containing pharmaceutically active compound wherein said firstamine containing pharmaceutical active compound is selected from thegroup consisting of racemic or single isomer ritalinic acid orphenethylamine derivatives, particularly methylphenidate andamphetamine, and said drug substance has a physical form selected fromamorphous and polymorphic; andA-B-C wherein A is a second amine containing pharmaceutically activecompound; C is an amine and B is a bidentate linking group used to linkA and C, and is defined by the formula:

wherein Y¹ and Y² are independently selected from nitrogen, oxygen andsulfur;G¹ and G² independently represent ionically or covalently bound groups;R¹⁰ and R¹¹ are present when necessary to satisfy the valence of Y¹ andY², respectively, and are independently selected from hydrogen and analkyl of 1-6 carbons; aryl of 6-12 carbons, alkylacyl of 1-8 carbons orarylacyl 7-15 carbons;R¹² and R¹³ are independently selected from hydrogen, alkyl or 1-6carbons, alkylacyl of 1-8 carbons or arylacyl of 7-15 carbons;R¹⁴ will replace one of R¹⁵, R¹⁶, R¹⁷ or R¹⁸ and one of R¹⁹, R²⁰, R²¹ orR²² and is an alkyl or branched alkyl of 1-10 carbons, aryl, arylalkylof 7-15 carbons and wherein R¹⁴ may include at least one opticallyactive carbon; andR¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹ and R²², are independently selectedfrom hydrogen, alkyl of 1-6 carbons, and wherein adjacent groups may betaken together to form a cyclic alkyl or cyclic aryl moiety.

Yet another embodiment is provided in a drug system comprising:

a first drug substance comprising a first amine containingpharmaceutically active compound with an immediate release profile toreach a therapeutic level; and

a second drug product comprising a second drug substance selected fromthe group consisting of:

a pharmaceutically acceptable organic acid addition salt of a secondamine containing pharmaceutically active compound wherein said secondamine containing pharmaceutical active compound is selected from thegroup consisting of:

-   methylphenidate and amphetamine wherein said drug substance has a    physical form selected from amorphous and polymorphic; and    A-B-C wherein A is a third amine containing pharmaceutically active    compound; C is an amine and B is a bidentate linking group used to    ionically or covalently link A and C, and is defined by the formula:

wherein Y¹ and Y² are independently selected from nitrogen, oxygen andsulfur;G¹ and G² independently represent ionically or covalently bound groups;R¹⁰ and R¹¹ are present when necessary to satisfy the valence of Y¹ andY², respectively, and are independently selected from hydrogen and analkyl of 1-6 carbons; aryl of 6-12 carbons, alkylacyl of 1-8 carbons orarylacyl 7-15 carbons;R¹² and R¹³ are independently selected from hydrogen, alkyl or 1-6carbons, alkylacyl of 1-8 carbons or arylacyl of 7-15 carbons;R¹⁴ will replace one of R¹⁵, R¹⁶, R¹⁷ or R¹⁸ and one of R¹⁹, R²⁰, R²¹ orR²² and is an alkyl or branched alkyl of 1-10 carbons, aryl, arylalkylof 7-15 carbons and wherein R¹⁴ may include at least one opticallyactive carbon; andR¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹ and R²², are independently selectedfrom hydrogen, alkyl of 1-6 carbons, and wherein adjacent groups may betaken together to form a cyclic alkyl or cyclic aryl moiety;wherein said second drug substance has a dissolution release profilesuitable for maintaining said therapeutic level from 1-24 hours.

Yet another embodiment is provided in a method for treating AttentionDeficit/Hyperactivity Disorder comprising:

prescribing a first drug product comprising a first drug substance at afirst dose to reach a first therapeutic level of the first drugsubstance wherein the first drug substance comprises a first aminecontaining pharmaceutically active compound with an immediate releaseprofile;monitoring results of the first dose to determine second dose;prescribing a second drug product comprising the first drug substance atthe second dose to reach a second therapeutic level wherein the seconddrug substance comprises the first amine containing pharmaceuticallyactive compound with the immediate release profile;monitoring results of the second dose to confirm suitability of thesecond dose;prescribing a third drug product comprising a second drug substancewherein the second drug substance has a dissolution release profilesuitable for maintaining the therapeutic level and the second drugsubstance is selected from the group consisting of:a pharmaceutically acceptable organic acid addition salt of a secondamine containing pharmaceutically active compound wherein the aminecontaining pharmaceutical active compound is selected from the groupconsisting of methylphenidate and amphetamine and said drug substancehas a physical form selected from amorphous and polymorphic; andA-B-C wherein A is a third amine containing pharmaceutically activecompound; C is an amine and B is a bidentate linking group used toionically or covalently link A and C, and is defined by the formula:

wherein Y¹ and Y² are independently selected from nitrogen, oxygen andsulfur;G¹ and G² independently represent ionically or covalently bound groups;R¹⁰ and R¹¹ are present when necessary to satisfy the valence of Y¹ andY², respectively, and are independently selected from hydrogen and analkyl of 1-6 carbons; aryl of 6-12 carbons, alkylacyl of 1-8 carbons orarylacyl 7-15 carbons;R¹² and R¹³ are independently selected from hydrogen, alkyl or 1-6carbons, alkylacyl of 1-8 carbons or arylacyl of 7-15 carbons;

R¹⁴ will replace one of R¹⁵, R¹⁶, R¹⁷ or R¹⁸ and one of R¹⁹, R²⁰, R²¹ orR²² and is an alkyl or branched alkyl of 1-10 carbons, aryl, arylalkylof 7-15 carbons and wherein R¹⁴ may include at least one opticallyactive carbon; and

R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹ and R²², are independently selectedfrom hydrogen, alkyl of 1-6 carbons, and wherein adjacent groups may betaken together to form a cyclic alkyl or cyclic aryl moiety.

Yet another embodiment is provided in a method for forming an improveddrug system with an optimized bioavailability comprising the steps of:

forming a drug substance consisting essentially of A-B-C wherein A is anamine containing pharmaceutically active compound; C is a firstdissolution modifying amine and B is a bidentate linking group used toionically or covalently link A and C, and is defined by the formula:

wherein Y¹ and Y² are independently selected from nitrogen, oxygen andsulfur;G¹ and G² independently represent ionically or covalently bound groups;R¹⁰ and R¹¹ are present when necessary to satisfy the valence of Y¹ andY², respectively, and are independently selected from hydrogen and analkyl of 1-6 carbons; aryl of 6-12 carbons, alkylacyl of 1-8 carbons orarylacyl 7-15 carbons;R¹² and R¹³ are independently selected from hydrogen, alkyl or 1-6carbons, alkylacyl of 1-8 carbons or arylacyl of 7-15 carbons;R¹⁴ will replace one of R¹⁵, R¹⁶, R¹⁷ or R¹⁸ and one of R¹⁹, R²⁰, R²¹ orR²² and is an alkyl or branched alkyl of 1-10 carbons, aryl, arylalkylof 7-15 carbons and wherein R¹⁴ may include at least one opticallyactive carbon; andR¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹ and R²², are independently selectedfrom hydrogen, alkyl of 1-6 carbons, and wherein adjacent groups may betaken together to form a cyclic alkyl or cyclic aryl moiety;measuring a dissolution profile at pH intervals representing gastric,intestinal and aqueous conditions;comparing said dissolution profile with a predetermined standard;forming a second drug substance consisting essentially of A-B-C′ whereinA is said amine containing pharmaceutically active compound; C′ is asecond dissolution modifying amine and B is said bidentate linking groupwherein said second dissolution modifying amine has a differenthydrophilicity than said first dissolution modifying amine.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is the differential scanning calorimetry (DSC) thermogram ofamorphous racemic-methylphenidate pamoate.

FIG. 2 is the Fourier Transform Infrared (FTIR) spectrum of amorphousracemic-methylphenidate pamoate.

FIG. 3 is the powder X-ray diffraction (PXRD) diffractogram of amorphousracemic-methylphenidate pamoate.

FIG. 4 is the differential scanning calorimetry (DSC) thermogram ofpolymorphic racemic-methylphenidate pamoate.

FIG. 5 is the Fourier Transform Infrared (FTIR) spectrum of polymorphicracemic-methylphenidate pamoate.

FIG. 6 is the powder X-ray diffraction (PXRD) diffractogram ofpolymorphic racemic-methylphenidate pamoate.

FIG. 7 is the differential scanning calorimetry (DSC) thermogram ofpolymorphic racemic-methylphenidate xinafoate.

FIG. 8 is the Fourier Transform Infrared (FTIR) spectrum of polymorphicracemic methylphenidate xinafoate.

FIG. 9 is the powder X-ray diffraction (PXRD) diffractogram ofpolymorphic racemic-methylphenidate xinafoate.

FIG. 10 is the differential scanning calorimetry (DSC) thermogram ofamorphous d-methylphenidate pamoate.

FIG. 11 is the Fourier Transform Infrared (FTIR) spectrum of amorphousd-methylphenidate pamoate.

FIG. 12 is the powder X-ray diffraction (PXRD) diffractogram ofamorphous d-methylphenidate pamoate.

FIG. 13 is the differential scanning calorimetry (DSC) thermogram ofpolymorphic d-methylphenidate pamoate.

FIG. 14 is the Fourier Transform Infrared (FTIR) spectrum of polymorphicd-methylphenidate pamoate.

FIG. 15 is the powder X-ray diffraction (PXRD) diffractogram ofpolymorphic d-methylphenidate pamoate.

FIG. 16 is the differential scanning calorimetry (DSC) thermogram ofamorphous d-methylphenidate xinafoate.

FIG. 17 is the Fourier Transform Infrared (FTIR) spectrum of amorphousd-methylphenidate xinafoate.

FIG. 18 is the powder X-ray diffraction (PXRD) diffractogram ofamorphous d-methylphenidate xinafoate.

FIG. 19 is the differential scanning calorimetry (DSC) thermogram ofamorphous dextro-amphetamine pamoate.

FIG. 20 is the Fourier Transform Infrared (FTIR) spectrum of amorphousdextro-amphetamine pamoate.

FIG. 21 is the powder X-ray diffraction (PXRD) diffractogram ofamorphous dextro-amphetamine pamoate.

FIG. 22 is the differential scanning calorimetry (DSC) thermogram ofpolymorphic dextro-amphetamine pamoate.

FIG. 23 is the Fourier Transform Infrared (FTIR) spectrum of polymorphicdextro-amphetamine pamoate.

FIG. 24 is the powder X-ray diffraction (PXRD) diffractogram ofpolymorphic dextro-amphetamine pamoate.

FIG. 25 is the differential scanning calorimetry (DSC) thermogram ofpolymorphic dextro-amphetamine xinafoate.

FIG. 26 is the Fourier Transform Infrared (FTIR) spectrum of polymorphicdextro-amphetamine xinafoate.

FIG. 27 is the powder X-ray diffraction (PXRD) diffractogram ofpolymorphic dextro-amphetamine xinafoate.

FIG. 28 is a graphical representation of the pH dependent dissolutionprofiles of amorphous racemic-methylphenidate pamoate.

FIG. 29 is a graphical representation of the dissolution profiles ofamorphous racemic-methylphenidate pamoate under acidic conditions as afunction of ethanol concentration.

FIG. 30 is a graphical representation of the pH dependent dissolutionprofiles of polymorphic racemic-methylphenidate pamoate.

FIG. 31 is a graphical representation of the dissolution profiles ofpolymorphic racemic-methylphenidate pamoate under acidic conditions as afunction of ethanol concentration.

FIG. 32 is a graphic representation of the pH dependent dissolutionprofiles of polymorphic racemic-methylphenidate xinafoate.

FIG. 33 is a graphical representation of the dissolution profiles ofpolymorphic racemic-methylphenidate xinafoate under acidic conditions asa function of ethanol concentration.

FIG. 34 is a graphical representation of the pH dependent dissolutionprofiles of polymorphic d-methylphenidate pamoate.

FIG. 35 is a graphical representation of the dissolution profiles ofpolymorphic d-methylphenidate pamoate under acidic conditions as afunction of ethanol concentration.

FIG. 36 is a graphical representation of the pH dependent dissolutionprofiles of amorphous d-methylphenidate pamoate.

FIG. 37 is a graphical representation of the dissolution profiles ofamorphous d-methylphenidate pamoate under acidic conditions as afunction of ethanol concentration.

FIG. 38 is a graphical representation of the pH dependent dissolutionprofiles of amorphous d-methylphenidate xinafoate.

FIG. 39 is a graphical representation of the dissolution profiles ofamorphous d-methylphenidate xinafoate under acidic conditions as afunction of ethanol concentration.

FIG. 40 is a graphical representation of the pH dependent dissolutionprofiles of polymorphic dextro-amphetamine pamoate.

FIG. 41 is a graphical representation of the dissolution profiles ofpolymorphic dextro-amphetamine pamoate under acidic conditions as afunction of ethanol concentration.

FIG. 42 is a graphical representation of the pH dependent dissolutionprofiles of amorphous dextro-amphetamine pamoate.

FIG. 43 is a graphical representation of the dissolution profiles ofamorphous dextro-amphetamine pamoate under acidic conditions as afunction of ethanol concentration.

FIG. 44 is a graphical representation of the pH dependent dissolutionprofiles of polymorphic dextro-amphetamine xinafoate.

FIG. 45 is a graphical representation of the dissolution profiles ofpolymorphic dextro-amphetamine xinafoate under acidic conditions as afunction of ethanol concentration.

FIG. 46 is the differential scanning calorimetry (DSC) thermogram ofpolymorphic racemic-methylphenidate stearylamine pamoate, 1:1:1 salt.

FIG. 47 is the Fourier Transform Infrared (FTIR) spectrum of polymorphicracemic-methylphenidate stearylamine pamoate, 1:1:1 salt.

FIG. 48 is the powder X-ray diffraction (PXRD) diffractogram ofpolymorphic racemic-methylphenidate stearylamine pamoate, 1:1:1 salt.

FIG. 49 is the proton nuclear magnetic resonance (¹H NMR) spectrum ofpolymorphic racemic-methylphenidate stearylamine pamoate, 1:1:1 salt.

FIG. 50 is the differential scanning calorimetry (DSC) thermogram ofamorphous d-methylphenidate mono-triethylammonium pamoate, 1:1:1 salt.

FIG. 51 is the Fourier Transform Infrared (FTIR) spectrum of amorphousd-methylphenidate mono-triethylammonium pamoate, 1:1:1 salt.

FIG. 52 is the powder X-ray diffraction (PXRD) diffractogram ofamorphous d-methylphenidate mono-triethylammonium pamoate, 1:1:1 salt.

FIG. 53 is the proton nuclear magnetic resonance (¹H NMR) spectrum ofamorphous d-methylphenidate mono-triethylammonium pamoate, 1:1:1 salt.

FIG. 54 is the differential scanning calorimetry (DSC) thermogram ofamorphous imipramine pamoate, 1:1 salt.

FIG. 55 is the Fourier Transform Infrared (FTIR) spectrum of amorphousimipramine pamoate, 1:1 salt.

FIG. 56 is the powder X-ray diffraction (PXRD) diffractogram ofamorphous imipramine pamoate, 1:1 salt.

FIG. 57 is the proton nuclear magnetic resonance (¹H NMR) spectrum ofamorphous imipramine pamoate, 1:1 salt.

FIG. 58 is the differential scanning calorimetry (DSC) thermogram ofamorphous imipramine mono-triethylammonium pamoate, 1:1:1 salt.

FIG. 59 is the Fourier Transform Infrared (FTIR) spectrum of amorphousimipramine mono-triethylammonium pamoate, 1:1:1 salt.

FIG. 60 is the powder X-ray diffraction (PXRD) diffractogram ofamorphous imipramine mono-triethylammonium pamoate, 1:1:1 salt.

FIG. 61 is the proton nuclear magnetic resonance (¹H NMR) spectrum ofamorphous imipramine mono-triethylammonium pamoate, 1:1:1 salt.

FIG. 62 is the differential scanning calorimetry (DSC) thermogram ofpolymorphic imipramine stearylamine pamoate, 1:1:1 salt.

FIG. 63 is the Fourier Transform Infrared (FTIR) spectrum of polymorphicimipramine stearylamine pamoate, 1:1:1 salt.

FIG. 64 is the powder X-ray diffraction (PXRD) diffractogram ofpolymorphic imipramine stearylamine pamoate, 1:1:1 salt.

FIG. 65 is the proton nuclear magnetic resonance (¹H NMR) spectrum ofpolymorphic imipramine stearylamine pamoate, 1:1:1 salt.

FIG. 66 is the differential scanning calorimetry (DSC) thermogram ofamorphous imipramine Jeffamine® pamoate, 1:1:1 salt.

FIG. 67 is the Fourier Transform Infrared (FTIR) spectrum of amorphousimipramine Jeffamine® pamoate, 1:1:1 salt.

FIG. 68 is the powder X-ray diffraction (PXRD) diffractogram ofamorphous imipramine Jeffamine® pamoate, 1:1:1 salt.

FIG. 69 is the proton nuclear magnetic resonance (¹H NMR) spectrum ofamorphous imipramine Jeffamine® pamoate, 1:1:1 salt.

FIG. 70 is the differential scanning calorimetry (DSC) thermogram ofamorphous hydrocodone stearylamine pamoate, 1:1:1 salt.

FIG. 71 is the Fourier Transform Infrared (FTIR) spectrum of amorphoushydrocodone stearylamine pamoate, 1:1:1 salt.

FIG. 72 is the powder X-ray diffraction (PXRD) diffractogram ofamorphous hydrocodone stearylamine pamoate, 1:1:1 salt.

FIG. 73 is the proton nuclear magnetic resonance (¹H NMR) spectrum ofamorphous hydrocodone stearylamine pamoate, 1:1:1 salt.

FIG. 74 is the differential scanning calorimetry (DSC) thermogram ofamorphous hydrocodone Jeffamine® pamoate, 1:1:1 salt.

FIG. 75 is the Fourier Transform Infrared (FTIR) spectrum of amorphoushydrocodone Jeffamine® pamoate, 1:1:1 salt.

FIG. 76 is the powder X-ray diffraction (PXRD) diffractogram ofamorphous hydrocodone Jeffamine® pamoate, 1:1:1 salt.

FIG. 77 is the proton nuclear magnetic resonance (¹H NMR) spectrum ofamorphous hydrocodone Jeffamine® pamoate, 1:1:1 salt.

FIG. 78 is a graphical representation of the pH dependent dissolutionprofiles of polymorphic racemic-methylphenidate stearylamine pamoate,1:1:1 salt.

FIG. 79 is a graphical representation of the dissolution profiles ofpolymorphic racemic-methylphenidate stearylamine pamoate, 1:1:1 saltunder acidic conditions as a function of ethanol concentration.

FIG. 80 is a graphical representation of the pH dependent dissolutionprofiles of amorphous d-methylphenidate mono-triethylammonium pamoate,1:1:1 salt.

FIG. 81 is a graphical representation of the dissolution profiles ofamorphous d-methylphenidate mono-triethylammonium pamoate, 1:1:1 saltunder acidic conditions as a function of ethanol concentration.

FIG. 82 is a graphical representation of the pH dependent dissolutionprofiles of amorphous imipramine pamoate, 1:1 salt.

FIG. 83 is a graphical representation of the dissolution profiles ofamorphous imipramine pamoate, 1:1 salt under acidic conditions as afunction of ethanol concentration.

FIG. 84 is a graphical representation of the pH dependent dissolutionprofiles of amorphous imipramine mono-triethylammonium pamoate, 1:1:1salt.

FIG. 85 is a graphical representation of the dissolution profiles ofamorphous imipramine mono-triethylammonium pamoate, 1:1:1 salt underacidic conditions as a function of ethanol concentration.

FIG. 86 is a graphical representation of the pH dependent dissolutionprofiles of polymorphic imipramine stearylamine pamoate, 1:1:1 salt.

FIG. 87 is a graphical representation of the dissolution profiles ofpolymorphic imipramine stearylamine pamoate, 1:1:1 salt under acidicconditions as a function of ethanol concentration.

FIG. 88 is a graphical representation of the pH dependent dissolutionprofiles of amorphous imipramine Jeffamine® pamoate, 1:1:1 salt.

FIG. 89 is a graphical representation of the dissolution profiles ofamorphous imipramine Jeffamine® pamoate, 1:1:1 salt under acidicconditions as a function of ethanol concentration.

FIG. 90 is a graphical representation of the pH dependent dissolutionprofiles of amorphous hydrocodone stearylamine pamoate, 1:1:1 salt.

FIG. 91 is a graphical representation of the dissolution profiles ofamorphous hydrocodone stearylamine pamoate, 1:1:1 salt under acidicconditions as a function of ethanol concentration.

FIG. 92 is a graphical representation of the pH dependent dissolutionprofiles of amorphous hydrocodone Jeffamine® pamoate, 1:1:1 salt.

FIG. 93 is a graphical representation of the dissolution profiles ofamorphous hydrocodone Jeffamine® pamoate, 1:1:1 salt under acidicconditions as a function of ethanol concentration.

FIG. 94 is the differential scanning calorimetry (DSC) thermogram ofamorphous bis(triethylammonium) pamoate.

FIG. 95 is the Fourier Transform Infrared (FTIR) spectrum of amorphousbis(triethylammonium) pamoate.

FIG. 96 is the powder X-ray diffraction (PXRD) diffractogram ofamorphous bis(triethylammonium) pamoate.

FIG. 97 is the proton nuclear magnetic resonance (¹H NMR) spectrum ofamorphous bis(triethylammonium) pamoate.

FIG. 98 is a graphical representation of the pH dependent dissolutionprofiles of d-methylphenidate hydrochloride.

FIG. 99 is a graphical representation of the dissolution profiles ofd-methylphenidate hydrochloride under acidic conditions as a function ofethanol concentration.

FIG. 100 is a graphical representation of the pH dependent dissolutionprofiles of racemic-methylphenidate hydrochloride.

FIG. 101 is a graphical representation of the dissolution profiles ofracemic-methylphenidate hydrochloride under acidic conditions as afunction of ethanol concentration.

FIG. 102 is a graphical representation of the pH dependent dissolutionprofiles of dextro-amphetamine sulfate.

FIG. 103 is graphical representation of the dissolution profiles ofdextro-amphetamine sulfate under acidic conditions as a function ofethanol concentration.

FIG. 104 is the differential scanning calorimetry (DSC) thermogram ofpolymorphic imipramine pamoate, 1:1 salt.

FIG. 105 is the Fourier Transform Infrared (FTIR) spectrum ofpolymorphic imipramine pamoate, 1:1 salt.

FIG. 106 is the powder X-ray diffraction (PXRD) diffractogram ofpolymorphic imipramine pamoate, 1:1 salt.

FIG. 107 is the proton nuclear magnetic resonance (¹H NMR) spectrum ofpolymorphic imipramine pamoate, 1:1 salt.

FIG. 108 is a graphical representation of the pH dependent dissolutionprofiles of polymorphic imipramine pamoate, 1:1 salt.

FIG. 109 is a graphical representation of the dissolution profiles ofpolymorphic imipramine pamoate, 1:1 salt under acidic conditions as afunction of ethanol concentration.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to improved pharmaceuticals,particularly, for use in treating AD(H)D. The improved pharmaceuticalsare abuse-deterrent, especially, with regards to abuse via alcoholenhanced dose dumping. The improved pharmaceuticals provide for animproved system of administration and an enhanced ability to design drugsubstances for optimized bioavailability through systematic dissolutionprofile alteration with selected hydrophilic and lipophilic properties.

The invention will be described with reference to figures which are anintegral, non-limiting, component of the specification.

The present invention provides compounds which are useful in thelegitimate and medically necessary treatment of ADD/ADHD. Morespecifically, the present invention provides for the isolation,identification and characterization of unique physical forms of organicacid addition salts of racemic or single isomer derivatives of ritalinicacid or phenethylamine derivatives, and particularly methylphenidate anddextro-amphetamine, where their use in treating ADD/ADHD is enhanced byrendering them abuse-deterrent. Furthermore, the present inventionprovides for the ability to adjust the hydrophilic and lipophiliccharacter of amine containing drug substances thereby allowing the drugdesigner to engineer a pre-determined dissolution profile of the drugsubstance. The advantages are provided through the synthetic ability tomanipulate and prepare drug substances with a myriad of substitutions.The present invention therefore provides a highly desirable technicalsolution to a complex pharmaceutical need and a government mandatedprogram.

The inventive drug substances, and drug product comprising the drugsubstances, are organic addition salts of an amine containing activepharmaceutical compound. In a particularly preferred embodiment theamine containing active pharmaceutical compound is selected from thegroup consisting of racemic or single isomer ritalinic acid orphenethylamine derivatives, particularly amphetamine and methylphenidatewherein the drug substance is in a physical form selected from amorphousand polymorphic.

The phenethylamine derivatives are defined by the structure:

wherein R⁶⁰ and R⁶¹ are independently selected from hydrogen, alkyl of1-15 carbons, cycloaliphatic and aromatic;R⁶² is selected from selected from hydrogen, alkyl of 1-15 carbons,cycloaliphatic and aromatic, benzyl and acetyl;R⁶³ is selected from alkyl of 1-15 carbons, halogen, alkoxy of 1-5carbons, benzyl, carbonyl and carboxyl; and* indicates an R or S carbon. Dextro-amphetamine is defined as R⁶⁰, R⁶¹,R⁶², and R⁶³ each being hydrogen and the remaining chiral center has anabsolute stereochemistry of S.

The ritalinic acid derivatives are defined by the structure:

wherein X is selected from O, N and S;R⁵⁰ is selected from hydrogen, alkyl of 1-15 carbons, cycloaliphatic andaromatic;R⁵¹ when necessary to balance the valence of X is selected fromhydrogen, alkyl of 1-15 carbons, cycloaliphatic and aromatic;R⁵³ is selected from selected from hydrogen, alkyl of 1-15 carbons,cycloaliphatic and aromatic, benzyl and acetyl;R⁵² and R⁵⁴ are independently selected from alkyl of 1-15 carbons,halogen, alkoxy of 1-5 carbons, benzyl, carbonyl and carboxyl; and* indicates an R or S carbon. d-methylphenidate is defined by X beingoxygen; R⁵⁰ not being necessary; R⁵¹ is methyl; R⁵², R⁵³ and R⁵⁴ arehydrogen and both stereochemical centers have an absolute configurationof R.

Where appropriate, optical isomers are specified herein by theirchirality in accordance with standard nomenclature using the termsdextro-, or d-, for dextrorotatory; levo-, or I, for levorotatory andracemic-, for mixed optical isomers. Also employed herein are thedesignations R and S which represent a stereochemical center's absoluteconfiguration.

The organic acid is described herein as either the acid or the linkinggroup with the understanding that the acid moiety reacts with an amineto form an ionic chemical bond. Throughout the specification the organicacid is represented, for convenience, as —COXR′R″, or an equivalent,wherein X, R′ and R″ are further defined or as —COY′R′″—, or theequivalent, wherein Y′ and R′” are further defined and the vacantvalency indicates a bond to a subsequent group. These definitions areused interchangeably for convenience of discussion.

An embodiment of the organic acid is defined by the following StructuresA through H wherein Structure A represents the general family ofcompounds embodied within the invention. Structure B represents thesubset of salicylic acid and its derivatives. Structures C, D and E areregio-isomeric variations of Compound A wherein two adjacentsubstituents on Compound A form a fused aryl ring (i.e. R¹+R²; R²+R³;and R³+R⁴). Structures F, G and H represent a further sub-category ofdimer-like compounds derived from Structure A. In Structure F,dimerization has occurred through R⁴ of two Structure A compounds withboth possessing fused-aryl ring systems formed via R²+R³. In StructureG, dimerization has again occurred through R⁴ of two Structure Acompounds; however both Structure A residues possess fused-aryl ringsystems formed via R¹+R².

Wherein R¹-R⁴ are independently selected from H, alkyl or substitutedalkyl of 1-6 carbons, adjacent groups may be taken together to form acyclic alkyl or cyclic aryl moiety; R⁵ represents H, alkyl, alkylacyl orarylacyl; R⁶ and R⁷ are independently selected from H, alkyl of 1-6carbons, aryl of 6-12 carbons, alkylacyl or arylacyl analoguessufficient to satisfy the valence of X (e.g. to provide a mixedanhydride or carbamate); X is selected from nitrogen, oxygen or sulfur,and when X=O, R⁶+R⁷ may represent an alkali earth cation, ammonium ortogether form a heterocyclic ammonium moiety;

Particularly preferred organic acids include Structures B through E.

wherein R⁵, R⁶, R⁷ and X remain as defined above for Structure A;

wherein X, R⁵, R⁶ and R⁷ remain as defined above for Structure A andmore preferably X is O;

wherein X, R¹, R², R⁵, R⁶ and R⁷ remain as defined above for Structure Aand more preferably X is O; R¹ and R² are hydrogen;

wherein X, R¹, R⁴, R⁵, R⁶ and R⁷ remain as defined above for Structure Aand more preferably X is O, R¹ and R⁴ are hydrogen;

wherein X, R¹, R⁵, R⁶ and R⁷ are independently defined as above forStructure A and more preferably at least one X is O and at least one R¹is hydrogen; and

wherein X, R⁵, R⁶ and R⁷ are independently defined as above forStructure A and more preferably X is O and R⁵ is hydrogen.

Pamoic acid, or a synthetic equivalent of pamoic acid, is the preferredembodiment. Pamoic acid has a formula corresponding to Structure Fwherein X is O; R¹, R⁵, R⁶ and R⁷ are hydrogen.

A synthetic equivalent of pamoic acid is a material that provides thestructural moiety independent of its particular salt, ester, or amideform and that upon pH adjustment yields pamoate functionality suitablefor reaction, optionally with one or two equivalents of anamine-containing active pharmaceutical ingredient to form a pamoatesalt. Examples of synthetic equivalents of pamoic acid capable ofmanipulation to produce pamoate salts include but are not limited to,disodium pamoate, mono-alkali pamoate, di-ammonium pamoate andderivatives (e.g. di-triethylammonium pamoate), di-potassium pamoate,lower molecular weight di-alkyl and/or di-aryl amine pamoate, lowermolecular weight di-alkyl and/or di-aryl esters of pamoic acid, andlower molecular weight di-alkylacyl and/or di-arylacyl O-esters ofpamoic acid, i.e. those alkylacyl and arylacyl esters formed using thehydroxyl moiety of pamoic acid and not the carboxylic acid functionalgroup. The descriptor phrase “lower molecular weight” used herein meansthe indicated moiety has a molecular mass contribution within thepamoate derivative of less than about 200 amu.

For clarity, the use of lower molecular weight di-alkyl or di-aryl aminepamoate allows for the exchange of higher molecular weight amines, or adrug's free base, to be exchanged for the lower molecular weight aminecomponent during the salt formation reaction. Similarly, the use oflower molecular weight di-alkylacyl and/or di-arylacyl pamoates allowfor their conversion through ester hydrolysis to the pamoic/pamoatemoiety followed by reaction with the desired drug free base.

A particularly preferred bis-functional, or bidentate, organic acidlinking group is defined by Structure H:

wherein Y¹ and Y² are independently selected from nitrogen, oxygen andsulfur;R¹⁰ and R¹¹ are present when necessary to satisfy the valence of Y¹ andY², respectively, and are independently selected from hydrogen; an alkylof 1-6 carbons; aryl of 6-12 carbons, alkylacyl of 1-8 carbons orarylacyl 7-15 carbons;G¹ and G² independently represent ionically or covalently bound groups;R¹² and R¹³ are independently selected from hydrogen, alkyl or 1-6carbons, alkylacyl of 1-8 carbons or arylacyl of 7-15 carbons;R¹⁴ will replace one of R¹⁵, R¹⁶, R¹⁷ or R¹⁸ and one of R¹⁹, R²⁰, R²¹ orR²² and is an alkyl or branched alkyl of 1-10 carbons, aryl, arylalkylof 7-15 carbons and wherein R¹⁴ may include at least one opticallyactive carbon; andR¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹ and R²², are independently selectedfrom hydrogen, alkyl of 1-6 carbons, and wherein adjacent groups may betaken together to form a cyclic alkyl or cyclic aryl moiety.

A particular advantage of bis-functional organic acids includes theability to attach separate amines to the organic acid at Y¹ and Y² (asthe amine salt of the bis-carboxylic acid). Two identicalpharmaceutically active compounds can be employed. For convenience ofdiscussion these are referred to herein as 2:1 compounds designating twopharmaceutically active compounds per one bis-organic acid. Similarly,one of the organic acid groups may remain as the acid while the otherforms a salt with a pharmaceutically active compound. For convenience ofdiscussion these are referred to herein as 1:1 compounds. In anotherembodiment one compound attached to the bis-functional organic acid maybe a pharmaceutically active compound with the other being an amine. Forconvenience these are referred to herein as 1:1:1 compounds. When abis-organic acid, such as represented by Structure H is utilized with anamine, the amine is preferably a pharmacophore or a dissolutionmodifying amine, both of which are more specifically described below.

Additional pharmaceutically active compounds which can be incorporatedwith the present invention include those selected from the groupconsisting of acetaminophen, caffeine, acetorphine, acetylmethadol,allylprodine, alphacetylmethadol, bufotenine, dextromoramide,diethyltryptamine, etorphine, heroin, ibogaine, ketobemidone, lysergicacid diethylamide, mescaline, methaqualone,3,4-methylenedioxyamphetamine, 3,4-methylenedioxymethamphetamine,N-ethyl-1-phenylcyclohexylamine, peyote,1-(1-phenylcyclohexyl)pyrrolidine, psilocybin, psilocin,1-{1-(2-thienyl)cyclohexyl}-piperidine, alphaprodine, anileridine,cocaine, dextropropoxyphene, diphenoxylate, ethylmorphine, glutethimide,hydrocodone, hydromorphone, levo-alpha-acetylmethadol, levorphanol,meperidine, methadone, morphine, opium, oxycodone, oxymorphone, poppystraw, thebaine, amphetamine, methamphetamine, methylphenidate,phencyclidine, codeine, benzphetamine, ketamine, alprazolam,chlorodiazepoxide, clorazepate, diethylpropion, fenfluramine,flurazepam, halazepam, lorazepam, mazindol, mebutamate, midazolam,oxazepam, pemoline, pentazocine, phentermine, prazepam, quazepam,temazepam, triazolam, zolpidem, buprenorphine, imipramine, apomorphine,dihydrocodeine, codeinone, thebaine, morphothebaine, thebenine,metathebainone, phenyldihydrothebaine, thebainhydroquinone,flavothebanone, alpha-codeimethine, acetylmethylmorphol,methylmorphenol, 14-hydroxycodeinone, sinomenine, dihydrosinomenine,hasubanonine, nalbuphine, nalmefene, naloxone, naltrexone, noscapine,oripavine and imipramine.

Particularly preferred pharmaceutically active compounds are selectedfrom the group consisting of methylphenidate, d-methylphenidate,amphetamine, dextro-amphetamine, hydrocodone, morphine, oxycodone,hydromorphone, oxymorphone, methadone, 14-hydroxycodeinone, phentermine,imipramine, codeine, naloxone, naltrexone, oripavine and thebaine.

In a preferred embodiment of the invention, at least one equivalent ofthe amine containing drug substance is reacted per mole of disodiumorganic acid salt to yield the drug substance. Occasionally, the chargeneutral amine species can be combined with organic acid in a solvent(e.g. DMF) to yield the desired salt. Preferably, 2:1, 1:1, or mixturesthereof, equivalents of amine per mole of organic acids are prepared.Typically, an aqueous acidic solution of the amine containing drugsubstance is combined with a basic solution of organic acid or disodiumsalt of the organic acid. Occasionally, the neutral species for eachreactant can be combined to form the desired salt. In either case, theacid/base reaction ensues and the insoluble organic acid saltprecipitates from the aqueous solution. Optionally, the salt can bepurified, dried and milled to obtain a drug substance ready forformulation into the desired delivery format.

The drug product formulated with the drug substances then possesses thetargeted delivery characteristics of the drug substance and thepotential for abuse of either the drug substance and/or drug product iseliminated or greatly reduced when abuse is attempted via the mucosalmembranes or by injection.

In one embodiment an amine containing pharmacophore can be utilized as asubstituent on the organic acid. Particularly preferred pharmacophoresinclude those selected from the group consisting of prostaglandins,benzyl derivatives; benzhydryl derivatives, phenethylamines;phenylpropylamines, arylacetic acids, arylpropionic acids,arylethylenes, monocyclic aromatic compounds, polycyclic aromaticcompounds, steroids, tetracyclines, acyclic compounds, five-memberedheterocycles, six-membered heterocycles, derivatives of morphine,derivatives of morphinan, derivatives of benzomorphan, phenylpiperidine,five-membered heterocycles fused to one benzene ring, six memberedheterocycles fused to one benzene ring, benzodiazepines, phenothizaines,dibenzopyrans, acridines, thioxanthenes, dibenzaepines,dihydrobenzaepines, dibenzazepines, dibenzoxepines, dibenzodiazepines,dibenzothiazepines, beta-lactam antibiotics, purines and pyrimidines.

In addition, synthetic methodology can be employed which allows for theisolation of the organic acid moiety uniquely substituted with theactive pharmaceutical ingredient and a dissolution modifying agent in aone-to-one ratio. The ability to isolate the single component from thepotentially-formed statistical reaction mixture allowed for theevaluation and comparison of the impact of hydrophilic and lipophilicdissolution modifying agents compared to the organic acid saltcontaining only the active ingredient.

Stearylamine is particularly suitable for demonstrating the introductionof lipophilic character to a molecule and a low molecular weightpolyethylene oxide (EO)/polypropylene oxide (PO) polymer possessingamino functionality is particularly suitable for demonstratingintroduction of hydrophilic character. The oleophilic nature of thestearylamine contrasted sharply to the hydrophilic, hydrogen bondingcapability of the EO/PO polymer. Particularly preferred amines fordemonstrating hydrophilic character are selected from the commerciallyavailable, amine containing Jeffamine® product line. Detailedinformation about the Jeffamine® series of polymers is found online.

Imipramine pamoate derivatives are particularly suitable fordemonstrating the utility of the invention with regards to incorporationof hydrophobic and hydrophilic enhancements.

Particularly preferred dissolution modifying amines are those consideredto be approved excipients by the United States Food and DrugAdministration, and/or are Generally Recognized as Safe (GRAS) listed,and/or used as food additives for oral consumption. More particularly,preferred dissolution modifying amines are those selected from the groupconsisting of primary amines, secondary amines, tertiary amines andquaternary amines and more particularly selected from the groupconsisting of aliphatic primary amines with 1-30 carbons; secondaryamines with 1-30 carbons; branched alkyl amines with 1-30 carbons andcyclic aliphatic amines with 1-30 carbons.

A particularly preferred dissolution modifying amine is defined by theformula:NR²³R²⁴R²⁵and R²³, R²⁴ and R²⁵ are independently selected hydrogen, alkyl of 1-60carbons; cyclic alkyl of 3-22 carbons; polyoxyalkylene with 1-5 carbonsper oxyalkylene monomeric unit or polyoxyarylene with 8-12 carbons peroxyarylene monomeric unit. In one embodiment at least one of R²³, R²⁴ orR²⁵ is not hydrogen. More preferably at least one of R²³, R²⁴ or R²⁵comprises a polymerized monomeric unit selected from the groupconsisting of ethylene oxide, propylene oxide, butylene oxide andstyrene oxide. In another embodiment at least one of the groups R²³, R²⁴or R²⁵ comprises a random or block copolymer comprising at least one ofpolymerized oxyalkylene monomeric units or polymerized oxyarylenemonomeric units also referred to in the art as polyetheramines. Inanother embodiment at least one of R²³, R²⁴ or R²⁵ comprises polymerizedmonomeric units selected from the group consisting of ethylene oxide,propylene oxide, butylene oxide and styrene oxide. In another embodimentat least one of R²³, R²⁴ or R²⁵ is defined by the formula:—(R²⁶—O)_(w)—(R²⁷—O)_(v)—R²⁸wherein R²⁶ and R²⁷ are independently selected from alkyl of 1-5 carbonsand aryl of 8-12 carbons;R²⁸ is an alkyl of 1-5 carbons; andw and v are integers independently selected to have a ratio of from 1:20to 20:1 and the molecular weight is at least 200 to no more than 3000.Yet another embodiment is defined by the formula:

wherein R⁴⁰, R⁴¹, R⁴² and R⁴³ are independently selected from hydrogen,alkyl of 1-6 carbons, aryl or 6-10 carbons, or arylalkyl of 7-11carbons,d, e and f are integers with each integer independently selected from 0to no more than 20 with the proviso that at least one integer selectedfrom d, e and f is at least 1; andR⁴⁴ and R⁴⁵ are independently selected from hydrogen, alkyl of 1-6carbons, aryl or 6-10 carbons, or arylalkyl of 7-11 carbons and

In another embodiment at least one of R⁴⁰, R⁴¹, R⁴² and R⁴³ is selectedfrom hydrogen, methyl, ethyl and phenyl. A particularly preferredembodiment is defined by the formula:

wherein:R³⁰ and R³¹ are independently selected from an alkyl of 1-5 carbons andmost preferably methyl;R³² and R³³ are independently selected from hydrogen andR³⁰—(O—CH₂CH₂)_(x)(OCH₂CHR³¹)_(y)—; andx and y are integers independently selected to have a ratio of from 1:20to 20:1 and said dissolution modifying amine has a molecular weight ofat least 200 to no more than 3000.

Particularly preferred dissolution modifying amines are selected fromthe group consisting of: JEFFAMINE® XTJ-505 (M-600); JEFFAMINE® XTJ-506(M-1000); JEFFAMINE® M-2005; JEFFAMINE® M2070; JEFFAMINE® D-230;JEFFAMINE® D-400; JEFFAMINE® D-2000; JEFFAMINE® D-4000 (XTJ-510);JEFFAMINE® HK-511; JEFFAMINE® ED-600 (XTJ-500); JEFFAMINE® ED-900(XTJ-501); JEFFAMINE® ED-2003 (XTJ-502); JEFFAMINE® EDR-148 (XTJ-504);JEFFAMINE® EDR-176 (XTJ-590); JEFFAMINE® T-403; JEFFAMINE® T-3000(XTJ-509); JEFFAMINE® T-5000; JEFFAMINE® SD-231 (XTJ-584); JEFFAMINE®SD-401 (XTJ-585); JEFFAMINE® SD-2001 (XTJ-576); JEFFAMINE® ST-404(XTJ-586); JEFFAMINE® XTJ-435; JEFFAMINE® XTJ-436; JEFFAMINE® XTJ-566and JEFFAMINE® XTJ-568. More preferably the dissolution modifying amineis selected from the group consisting of: JEFFAMINE® XTJ-505 (M-600);JEFFAMINE® XTJ-506 (M-1000); JEFFAMINE® M-2005 and JEFFAMINE® M2070.

Particularly preferred materials are defined by the structure:

wherein R, X and Y are provided in Table 1.

TABLE 1 Approximate Commercial Name R Y/X MW JEFFAMINE ® XTJ-505 (M-600)Methyl  9:1  600 JEFFAMINE ® XTJ-506 (M-1000) Methyl  3:19 1,000JEFFAMINE ® M-2005 Methyl 29:6  2,000 JEFFAMINE ® M2070 Methyl 10:312,000

The most preferred amines are octadecylamine (stearylamine) andpolyoxyalkylene amine (Jeffamine XTJ-505®) as representing a range ofhydrophobic to hydrophilic amines, respectively.

In another embodiment the dissolution modifying amine is selected fromthe group consisting of methyl amine; ethyl amine; propyl amine; butylamine; pentyl amine; hexyl amine; octyl amine; nonyl amine; decyl amine;undecyl amine; octadecyl amine; hexadecyl amine; di-dodecyl amine;dimethyl amine, diethyl amine; dipropyl amine; dibutyl amine; dipentylamine; dihexyl amine; dicyclohexyl amine; diheptyl amine; dioctyl amine;didecyl amine; dioctadecyl amine; didodecyl amine; cyclohexyl amine;2,3-dimethyl-1-cyclohexylamine; piperidine; morpholine; pyrrolidine;aniline; anisidine; rosin amine, dehydroabietyl amine; dihydroabietylamine; hydroabietyl amine; adamantyl amine; isonipecotamide;polyoxyalkylenemonoamine wherein each oxyalkylene independently comprise1-5 carbons; polyoxyalkylenediamine wherein each oxyalkyleneindependently comprise 1-5 carbons; polyoxyalkylenetriamine wherein eachoxyalkylene independently comprise 1-5 carbons;3,3′-diamino-N-methyl-dipropylamine; polyethylene imine; ethylenediamine; hexamethylene diamine; cyclohexyldiamines; 1,3-pentadiamine;1,12-dodecanediamine; 3-dimethylaminopropylamine;4,7,10-trioxa-1,13-tridecanediamine; diethylene triamine;3,3-diamino-N-methyldipropylamine; tris(2-aminoethyl)amine;tridecylamine; pentadecylamine; hexadecylamine; heptadecylamine;octadecylamine; monodecylamine; eicosylamine; heneicosylamine;docosylamine; tricosylamine; tetracosylamine; pentacosylamine;hexacosylamine; laurylamine; myristylamine; palmitylamine; stearoamine;arachidylamine; behenylamine; lignocerylamine; lauroleylamine;myristoleylamine; palmitoleyamine; gadoleylamine; erucylamine;ricinoleylamine; linoleylamine; linolenylamine; eleostearoamine;arachidonylamine; clupanodylamine; di-dodecylamine; di-tridecylamine;di-pentadecylamine; di-hexadecylamine; di-heptadecylamine;di-octadecylamine; di-monodecylamine; di-eicosylamine;di-heneicosaneamine; di-docosylamine; di-tricosylamine;di-tetracosylamine; di-pentacosylamine; di-hexacosylamine;di-laurylamine; di-myristylamine; di-palmitylamine; di-stearoamine;di-arachidylamine; di-behenylamine; di-lignocerylamine;di-lauroleylamine; di-myristoleylamine; di-palmitoleyamine;di-gadoleylamine; di-erucylamine; di-ricinoleylamine; di-linoleylamine;di-linolenylamine; di-eleostearoamine; di-arachidonylamine; anddi-clupanodylamine; tri-dodecylamine; tri-tridecylamine;tri-pentadecylamine; tri-hexadecylamine; tri-heptadecylamine;tri-octadecylamine; tri-monodecylamine; tri-eicosylamine;tri-heneicosylamine; tri-docosylamine; tri-tricosylamine;tri-tetracosylamine; tri-pentacosylamine; tri-hexacosylamine;tri-laurylamine; tri-myristylamine; tri-palmitylamine; tri-stearylamine;tri-arachidylamine; tri-behenylamine; tri-lignocerylamine;tri-lauroleylamine; tri-myristoleylamine; tri-palmitoleyamine;tri-gadoleylamine; tri-erucylamine; tri-ricinoleylamine;tri-linoleylamine; tri-linolenylamine; tri-eleostearylamine;tri-arachidonylamine; tri-clupanodylamine; meglumine and amino-glucose.

A particularly preferred dissolution modifying amine is selected fromthe group consisting of n-propyl amine; iso-propyl amine; n-butyl amine,iso-butyl amine; s-butyl amine; t-butyl amine; n-pentyl amine,iso-pentyl amine, t-pentyl amine; n-hexyl amine, iso-hexyl amine,t-hexyl amine; n-octyl amine, iso-octyl amine, t-octyl amine; n-nonylamine, iso-nonyl amine, t-nonyl amine; n-decyl amine; branched decylamine; n-undecyl amine, branched undecyl amine; n-octadecyl amine,branched octadecyl amine; n-hexadecyl amine, branched hexadecyl amine;n-dodecyl amine, branched dodecyl amine; dimethyl amine, diethyl amine;di-n-propyl amine; di-isopropyl amine; di-n-butyl amine, di-iso-butylamine, di-t-butyl amine; di-n-pentyl amine; di-isopentyl amine;di-t-pentyl amine; di-n-hexyl amine; di-iso-hexyl amine; di-t-hexylamine; di-n-cyclohexyl amine; di-iso-cyclohexyl amine; di-t-cyclohexylamine; di-n-heptyl amine; di-iso-heptyl amine; di-t-heptyl amine;di-n-octyl amine, di-isooctyl amine; di-t-octyl amine; di-n-decyl amine;di-iso-decyl amine; di-t-decyl amine; di-n-octadecyl amine;diisooctadecyl amine; di-t-octadecyl amine; di-n-dodecyl amine;di-isododecyl amine; di-t-dodecyl amine; tri-n-propyl; tri-isopropylamine; tri-n-butyl amine; tri-isobutyl amine; tri-t-butyl amine;tri-n-pentyl amine; tri-iso-pentyl amine, tri-t-pentyl amine;tri-n-hexyl amine, tri-isohexyl amine; tri-t-hexyl amine; tri-cyclohexylamine; tri-n-heptyl amine; tri-iso-heptyl amine and tri-t-heptyl amine.

Amino alcohol precursors are particularly preferred amines. The aminoalcohol precursors include any compound that contains at least onealcohol functional group and at least one amine functional group. Thepreferred classes of amino alcohols are monoalkanol amines and dialkanolamines and can include trialkanol amines and combinations thereof.Examples of amino alcohols include ethanolamine;3-amino-1,2-propanediol; serinol; 2-amino-2-methyl-1,3-propanediol;tris(hydroxymethyl)-aminomethane; 1-amino-1-deoxy-D-sorbitol;diethanolamine; diisopropanolamine; N-methyl-N,N-diethanolamine;triethanolamine; and N,N,N′,N′-tetrakis (2-hydroxypropyl)ethylenediamine and combinations thereof.

The organic acid component to the salt forming process also imparts adrug delivery performance feature for selective absorption. It has beenreported by Bristol et al. that the organic acid addition salts areessentially insoluble in the mucosal membranes. However, if the ActivePharmaceutical Ingredient (API) organic acid addition salt is subjectedto the gastrointestinal tract where it encounters low pH conditions, theactive ingredient is released. In this regard, the selective release isaccomplished by pH conditions. Conversely, the use of organic acidaddition salts may also be used to selectively deliver amine-containingdrug substances wherein the driving force is not a pH change, but analteration of the hydrophilic/lipophilic balance of the amine-containingAPI. An analogy to this concept is represented by the work reported byAcura Pharmaceuticals and Collegium.

In regard to Collegium's effort to impart abuse deterrent properties tocontrolled substances, an abuse-deterrent pharmaceutical composition isdescribed in United States Patent Application Publication Number US2004/0052731 A1 [Hirsh et al.], the disclosure of which is incorporatedherein by reference in its entirety. The publication indicates theintention to alter the lipophilicity of an opioid drug substance bycomplexation with oleophilic metal salts such as zinc stearate. It issuggested that the “likelihood of improper administration of drugs,especially drugs such as opioids” would be due to the increase inlipophilicity imparted to the opioid by the complexation with said metalsalts.

In U.S. Pat. No. 7,201,920 B2 [Kumar et al.] assigned to AcuraPharmaceuticals, the disclosure of which is incorporated herein in itsentirety, the inventors describe a formulation technique to prepareabuse deterrent dosage forms of opioid analgesics by employing apolyethylene oxide polymer to form a matrix.

In regard to Acura's work, the gel forming tendency of the hydrophilicpolyethylene oxide polymer was selected essentially to perform as adesiccant. The opioid is formulated with the polymer and any attempt toabuse the drug by snorting would yield a globular gel in the mucosalmembranes of the nose and thus deny the “high” sought by the abuser. Incontrast, Collegium reports forming a complex with the opioid using analkyl substituted metal, such as zinc stearate. The resulting complexincreases the hydrophobicity of the otherwise water soluble opioid. Asdrug abusers attempt to snort the hydrophobic opioid complex, itallegedly does not provide the desired result to the abuser. For bothAcura and Collegium the approach was to provide a selective drug releaseprofile to thwart drug abuse by using a chemical drug deliverymechanism; Acura used a formulation technique while Collegium modifiedthe API properties. Both methods however are fundamentally dependentupon altering the hydrophilic/lipophilic balance of the opioid and toallow its release only when used for legitimate purposes. With Acura'sapproach, the hydrophilic nature of the opioid, or amine containing drugsubstance, is competitively defeated by adding the highly hydrophilicpolyethylene oxide polymer. With Collegium's approach, the hydrophilicnature of the opioid is reduced by adding an oleophilic residue viacomplexation chemistry through a metal ion.

One aspect of the invention herein is to utilize organic acid additionsalts as a drug delivery platform at the molecular level. A drugdelivery platform as used herein is defined as a means to deliver anactive pharmaceutical ingredient according to “time, manner, and place”,wherein:

-   -   a) the time component impacts the pharmacokinetic release of the        drug substance;    -   b) the manner component relates to mechanism of release from the        drug delivery system; and    -   c) the place component refers to the location in the        physiological system where release begins to occur and extends        for the duration of the release.

Herein, drug delivery systems are described employing thebis-functionality of a bis-functional organic acid moiety to carry boththe active pharmaceutical ingredient and a dissolution modifyingcomponent within the same molecule. To elaborate, the bis-functionalorganic acid moiety was reacted with an equivalent of amine-containingactive pharmaceutical ingredient and with an equivalent of anamine-containing dissolution modifying agent. In this manner thebis-functional salts formed would be in a statistical distribution ofpotential compounds depending upon the comparative reactivities andmolar ratios of amine-containing active pharmaceutical ingredient andamine-containing polymer component used to form the bis-functionalizedsalt. When an equivalent of each amine is used having equivalentreactivities, one would expect the statistical ratio of organic acidentities to encompass: 25 molar % bis-functional organic acidsubstituted only with active ingredient; 50 molar % bis-functionalorganic acid substituted with one each of the active ingredient and thedissolution modifying amine, and lastly, 25 molar % bis-functionalorganic acid substituted entirely with the dissolution modifying agent.This bulk mixture exhibits desired drug delivery properties anddissolution profiles otherwise unachievable.

The pH of the gastrointestinal tract essentially remains highly acidicwith the exception of the lower colon which reaches pH 8; vaginal pH istypically around 5.8 and the nasal cavity is approximately pH 4.5. Moregenerally, each of the mucosal membranes, particularly ocular, nasal,pulmonary, buccal, sublingual, gingival, rectal and vaginal, arereceptive to drug absorption if release can occur. A feature of thepresent invention is the ability to provide drug substances withretarded release of the controlled substance, particularlyamine-containing pamoate salt (or related salt family) in the pH rangeof about 4 to 9 which encompasses the physiological pH of the mucosa.These release properties were an unexpected finding recognized andobserved after performing dissolution tests over a wide pH range onseveral unrelated compounds. The release properties and saturationsolubility profiles are a means to evaluate a reasonable dosageapplication to the mucosa. The non-release of the drug in the 4 to 9 pHrange negates absorption and prevents the physical act of abuse. For theamine-containing hydrochloride salts, an abuse mechanism remainsoperative since these salts do not exhibit the discriminating “on/off”switch of the present invention.

An experimental refinement of the dissolution tests was performed onseveral compounds to better represent the physiological conditionsencountered during abuse attempts and to account for the saturationsolubility factor. Further, control experiments were included in theexperimental design to compare the organic acid addition salts of thecurrent invention with the hydrochloride salts of identicalamine-containing controlled substances. In some cases, model compoundswere used to demonstrate the principles of the invention instead ofusing compounds legally designated as controlled substances.Side-by-side dissolution experiments on hydrochloride salts versus thoseof the present invention were conducted at three different pHconditions: a) a pH of about 1 to simulate gastric conditions, b) pH ofabout 4.5 to simulate mucosal membrane pH, and c) a pH of about 7 toevaluate a potential pH range of mucosal membranes and blood pH forpurposes of simulating injection. In addition, the experimentation wasdesigned to demonstrate the equivalence of the organic acid additionsalts to the mineral acid salts if used by their intended route of oraladministration route and hence the concentration effects were includedin the study. For oral administration of a dosage form, the UnitedStates Pharmacopeia (USP) recommends the immediate release testingprocedure on a unit dosage to be performed on a simulated stomach“solution” volume of 900 mL. Besides temperature, pH and concentration,the time factor was also evaluated under the presumption that anindividual abusing a drug will want to obtain their anticipatedphysiological response within an hour or less.

Immediate release is defined as a drug substance wherein under simulatedgastric conditions at least 85% is released within 30 minutes.

For the purposes of the present application, dose dumping is consideredto be mitigation if under simulated gastric conditions, represented by0.1 N HCl, any of the following conditions are met: a) no more thanabout 35% of an active pharmaceutical is released at 30 minutes with atleast 5% ethanol present; b) the percentage of active pharmaceuticalreleased with at least 5% ethanol present is no more than the percentageof active pharmaceutical released with no alcohol present; or c) thepercentage of drug substance released with 40 wt % ethanol in 0.1 N HCldoes not exceed 60% while the percentage of drug substance releasedunder the conditions selected from water, 0.1 N HCl, 5 wt % ethanol in0.1 N HCl and 20 wt % ethanol in 0.1 N HCl does not exceed the drugsubstance released with 40 wt % ethanol in 0.1 N HCl. It is particularlypreferred that no more than about 35% of the active pharmaceutical bereleased over an extended time, such as at least 45 minutes.

The dissolution profiles are best understood by their organization intothree broad categories. The first category consists of the existing,currently commercialized drug substances d-methylphenidatehydrochloride, racemic-methylphenidate hydrochloride anddextro-amphetamine sulfate. For each drug substance an intrinsic pHdependent dissolution profile and a corresponding dose dumping profilewere performed. The second category contains drug substances prepared astheir pamoate (which are representative of a bis-functional organic acidsalt) and xinafoate salts. This second category is exemplified by theintrinsic and dose dumping profiles for a selection of amorphous andpolymorphic forms of d-methylphenidate pamoate; d-methylphenidatexinafoate, racemic-methylphenidate pamoate, racemic-methylphenidatexinafoate, dextro-amphetamine pamoate and dextro-amphetamine xinafoate.

The third category of dissolution profiles is exemplified by controlleddissolution profiles of organic acid salts by: 1) selection of thestoichiometric proportions of the free-base drug substance to thebis-functional organic acid moiety such as 2:1 vs. 1:1 drug substancebase:bis-functional organic acid moiety; 2) the effect arising frommixed bis-functional organic acid salts with a 1:1:1 ratio of drugsubstance base:bis-functional organic acid moiety:functional amine, and3) the impact of matching the physical properties of a drug substancebase with a functional amine, both coupled as a salt to thebis-functional organic acid moiety. This third category contains theintrinsic and dose dumping profiles demonstrated for a selection ofamorphous and/or polymorphic forms of imipramine pamoate (1:1);imipramine triethylammonium pamoate (1:1:1); imipramine Jeffamine®pamoate (1:1:1); imipramine stearyl amine pamoate (1:1:1); hydrocodoneJeffamine® pamoate (1:1:1); hydrocodone stearyl amine pamoate (1:1:1);d-methylphenidate triethylammonium pamoate (1:1:1); andracemic-methylphenidate stearylamine pamoate (1:1:1).

The intrinsic pH dissolution and dose dumping profiles of the firstcategory provide the motivation for establishing a chemical methodologyfor imparting abuse-deterrent performance features to the active, drugsubstance moiety. Not surprisingly, drug product development hashistorically depended upon the incorporated drug substance to be freelywater soluble as a condition of bioavailability. The active ingredientsd-methylphenidate hydrochloride, racemic-methylphenidate hydrochlorideand dextro-amphetamine sulfate are all freely soluble in water and theirpH and dose dumping dissolution profiles confirm this observation. FIG.98 is the dissolution profile and FIG. 99 the dose dumping profile ford-methylphenidate hydrochloride. FIG. 100 is the dissolution profile andFIG. 101 the dose dumping profile for racemic-methylphenidatehydrochloride. FIG. 102 is the dissolution profile and FIG. 103 is thedissolution profile for dextro-amphetamine sulfate. The results reflectthe formulation difficulty in providing these drug substances in a formthat is abuse deterrent. The active ingredient as the mineral acid saltis readily available under nearly any aqueous condition and the need tomodify the drug substance's dissolution properties is apparent in orderto provide an abuse deterrent feature. In recent years, this concept hasbeen significantly challenged by advanced drug substances having poorwater solubility and thus, a higher burden placed on the formulator toachieve the desired dissolution profile of the drug product as monitoredby the dissolution profile behavior of the drug substance.

Exemplars within the second category establish the basis satisfying theneed to impart abuse-deterrent features to the active, drug substancemoieties. Without imposing limitation to the invention, the particularactive, drug substance exemplars illustrated herein included-methylphenidate, racemic-methylphenidate and dextro-amphetamine astheir amorphous or polymorphic salts selected from the salt forming acidfamilies of Formula H with pamoates (as 2:1, or 1:1:1 salts) orxinafoates being most preferred embodiments. For ease of comparisonbetween amorphous or polymorphic forms of the same drug substance, boththe intrinsic pH dissolution and dose dumping profiles of one physicalform should be compared to the comparable profiles of a second form ofthe drug substance salt. Throughout this discussion this approach willbe used in order to fully reveal the depth and breadth of the invention.For these paired comparisons, the following nomenclature is used whendescribing the intrinsic pH dissolution and dose dumping profiles. For agiven drug substance evaluation, Figures A/B will mean Figure A is theintrinsic pH dissolution profile and Figure B is the corresponding dosedumping profile of the same drug substance. In this manner Figures A/Bare readily compared with Figures C/D which may be a differentpolymorphic form of the same drug substance, or a different, butanalogous drug substance. By way of example, amorphous and polymorphicd-methylphenidate pamoate are readily compared by comparing FIGS. 36/37with FIGS. 34/35, respectively. The polymorphic form exhibits adesirable dose dumping profile particularly with the 40% ethanolcondition leveling out at about 20% release of the active moiety. Thisresult also indicates ethanol extraction of the active ingredient from aformulated drug product is impeded. The polymorphic form also exhibits alinear response under the 0.1 N HCl condition (simulated gastriccondition) and is preferable to an immediate release response observedfor the corresponding hydrochloride salt as shown in FIGS. 98/99.Further, and from analysis of these paired comparisons, the amorphousform of d-methylphenidate pamoate exhibits a slightly faster rate ofrelease at the 0.1 N HCl condition, but “fails” the dose dumping testsince the presence of 5% ethanol appears to accelerate the release ofthe drug substance at a rate faster than in the simulated gastriccondition. From this analysis, polymorphic d-methylphenidate pamoateexhibits the properties desired for an abuse-deterrent drug substancesuitable for incorporation into a formulated drug product.

The results from the d-methylphenidate pamoate polymorphic series can becompared with those from amorphous and polymorphicracemic-methylphenidate pamoate by examination of FIGS. 28/29 and FIGS.30/31, respectively. The pH dissolution profiles of the amorphousracemic salt, FIG. 28, are quite similar to the profiles obtained forthe polymorphic d-methylphenidate pamoate as shown in FIG. 34. The dosedumping profile for this amorphous form, FIG. 29, is quite similar tothe polymorphic single isomer drug substance, as illustrated in FIG. 35.Similarly, the polymorphic racemic salt, FIGS. 30/31, exhibits pHdissolution and dose dumping profiles highly comparable to the singleisomer, polymorphic d-methylphenidate pamoate, as seen in FIGS. 34/35.As a result of these comparisons for the methylphenidate pamoate series(single isomer vs. racemate vs. the available amorphous/polymorphicforms of each), the preferred abuse-deterrent compound is polymorphicd-methylphenidate pamoate.

Upon changing the salt forming family, anomalous, unexpected results areobtained for amorphous d-methylphenidate xinafoate as observed in FIGS.38/39. First, the pH dissolution profile, FIG. 38, indicates a pH 4.5condition provides a faster release rate than the 0.1 N HCl condition.Typically, the lower pH condition has been observed to yield the fastestrelease of the active ingredient from its organic acid addition saltcontrary to this present finding. Indeed, the higher pH conditionsaccelerate the active's release with the 0.1 N HCl condition parallelingthe release rate observed in water only. This unexpected finding wouldindicate d-methylphenidate xinafoate could pass from the stomach to theintestinal tract before being completely released. In contrast, when thedrug substance was subjected to the dose dumping regimen, all conditionsinhibited dose dumping except the 40% ethanol solution which enabledapproximately 60% release of the active ingredient after about thirtyminutes. This result indicates ethanol could promote dose dumping of thedosage and potentially, aid in the extraction of the active amine from adosage form.

The amorphous, single isomer d-methylphenidate xinafoate (FIGS. 38/39)was compared with the polymorphic racemic methylphenidate xinafoate(FIGS. 32/33). A very favorable pH dissolution profile was obtainedwherein for amorphous d-methylphenidate xinafoate (FIG. 38) the 0.1 NHCl condition provided a gradual linear release. For polymorphic racemicmethylphenidate xinafoate, there was observed release suppression at thehigher pH conditions (FIG. 32). The dose dumping profile was also quitefavorable wherein less than twenty percent of the active was releasedafter thirty minutes (at any condition) for polymorphic racemicmethylphenidate xianfoate (FIG. 33). Only after about ninety minutes didthe forty percent ethanol condition deviate from the 0.1 N HCl conditionand exhibit any accelerated release (FIG. 33). Under practicalabuse-deterrent considerations, a potential drug abuser intent onemploying dose dumping to get “high” would be disappointed with a ninetyminute delay.

To summarize, from the paired comparisons of the three categories: 1)single isomer vs. racemic-methylphenidate 2) their organic acid additionsalt family (pamoate vs. xinafoate); and 3) the amorphous vs.polymorphic forms of each, a rank order was established for impartingabuse-deterrent features to methylphenidate. The most preferredembodiment is polymorphic d-methylphenidate pamoate, followedessentially equally by polymorphic racemic-methylphenidate pamoate andpolymorphic racemic-methylphenidate xinafoate. A full consideration ofphysiological properties and FDA regulatory preference would furthersupport the selection of polymorphic d-methylphenidate pamoate as thepreferred drug substance form.

Dextro-amphetamine is another important active ingredient in the arsenalto treat ADD or ADHD, yet this active ingredient is also quitesusceptible to abuse. Analogous to the methylphenidate investigationabove, the present invention demonstrated the use of organic acidaddition salts to impart abuse-deterrent features to dextro-amphetamine.Here too, the organic acid addition salt family was compared with theavailable amorphous and polymorphic forms. Specifically, the pHdissolution and dose dumping profiles of amorphous dextro-amphetaminepamoate, as realized from the results presented in FIGS. 42/43, arecompared with the polymorphic form of the drug substance as presented inFIGS. 40/41. Minor differences were observed in these paired comparisonsand either amorphous or polymorphic forms of dextro-amphetamine pamoateexhibit excellent abuse-deterrent capability. In particular, eachexhibits a linear release of the active ingredient at the 0.1 N HClcondition and an inhibition of dose dumping at all ethanolconcentrations.

Similar to the xinafoate salt of d-methylphenidate, polymorphicdextro-amphetamine xinafoate was subjected to the pH dissolution anddose dumping regimens with the results captured in FIGS. 44/45. Veryunexpected results were obtained with this xinafoate salt wherein the0.1 N HCl condition (the gastric condition) suppressed release of theactive ingredient. Higher pH conditions (e.g. pH 4.5) provided for arestrained, but relatively quick release rate (approximately eightypercent release after sixty minutes). For dose dumping, the twenty andforty percent ethanol conditions led to about thirty-five percentrelease of the active after only thirty minutes compared to essentiallyno release of the active under the gastric condition. Clearly, ananomaly exists in the xinafoate's ability to impart predictable abusedeterrent features to an amine containing active ingredient. Thisemphasizes the unique ability of the pamoate salts to provide protectionto the non-therapeutic use (i.e. abuse) of controlled substances.Interestingly, the faster release profiles of the xinafoate salts (atthe higher pH conditions) provided a means for release of the activeingredient in the intestinal tract and avoided release in the low pHstomach. Hence, a combination of pamoate and xinafoate salts of a givenamine containing controlled substance would provide for a tunable andtargeted release profile in a dosage form and enhance the stability oflow pH sensitive drugs.

Since the bis-functional organic salts, e.g. the pamoate salts,exhibited the preferential ability to impart abuse-deterrent features toamine containing controlled substances, further manipulation of thebis-functional organic moiety was accomplished while retaining saltformation with the amine-containing active ingredient. The di-basicfunctionality of the exemplary moiety set forth in Formula H allowsformation of a mixed salt from two different amines, one of which is anactive ingredient. Imipramine is exemplary for evaluating the depth andbreadth of the invention's chemical aspects. Synthetically, thedifficulty arises in preparing the desired mixed salt within onemolecule and avoiding preparation of a statistical mixture of saltsincluding the bis-functional moiety possessing two equivalents of amineactive pharmaceutical ingredient and another bis-functional organicmoiety consisting of salt formation with two equivalents of a secondamine which functions as a dissolution modifier.

To achieve the desired synthetic goal of a mixed salt, two differentsynthetic methods were employed. One synthetic method entailedpreparation of imipramine pamoate mono-triethylammonium salt by reactionof one equivalent of imipramine hydrochloride with di-triethylammoniumpamoate. Subsequently, two other amines (stearylamine or Jeffamine®)could then react with imipramine pamoate mono-triethylammonium salt toform the desired 1:1:1 mixed salts. On a side note, if just the 1:1 saltof imipramine (free carboxylic acid group) is desired, mono-imipraminepamoate could also be prepared from deprotection of imipramine pamoatemono-triethylammonium salt or, in an entirely unrelated reaction, byreaction of 1:1 Tetronic® pamoate with imipramine pamoate (2:1). Thesecond synthetic method entailed displacement of one of the imipraminesof di-imipramine pamoate with one of the two other amines mentionedabove (stearylamine or Jeffamine®).

Consequently, the analogues of mono-imipramine pamoate salts prepared asexemplars from the first synthetic method demonstrating the conceptincluded: amorphous imipramine triethylammonium pamoate. Exemplars ofthe first synthetic method can also be applied to the d-methylphenidatepamoate series where d-methylphenidate pamoate mono-triethylammoniumsalt can be prepared from reaction of d-methylphenidate hydrochloridewith di-triethylammonium pamoate.

The analogue pamoate salts prepared as exemplars from the secondsynthetic method demonstrating the concept included: amorphousimipramine Jeffamine® pamoate and polymorphic imipramine stearylaminepamoate.

Exemplars of the second synthetic method can also be applied to otheranalogous amine pamoates: 1) the racemic methylphenidate pamoate serieswhere racemic methylphenidate pamoate (2:1) is reacted with oneequivalent of stearylamine to provide polymorphic methylphenidatestearylamine pamoate (1:1:1), 2) the hydrocodone series wherehydrocodone pamoate (2:1) is reacted with one equivalent of stearylamineto provide mostly amorphous hydrocodone stearylamine pamoate (1:1:1) and3) the hydrocodone series where hydrocodone pamoate (2:1) is reactedwith one equivalent of Jeffamine® to provide amorphous hydrocodoneJeffamine® pamoate (1:1:1). These will be expounded on later.

Each of these compounds was analytically characterized and subjected tothe pH and dose dumping dissolution regimens to determine theirperformance characteristics. The findings were contrary to theanticipated results. The free carboxyl group within the pamoic acidmoiety is comparatively insoluble under lower pH conditions whileincorporation of the triethylammonium salt would increase itssolubility. Improving the hydrophilic character of the pamoic acidmoiety by substitution with a polyoxyalkylene (Jeffamine) should alsoenhance the pamoate/pamoic acid moiety's solubility. In contrast, thehydrophobic stearylamine salt of the pamoate/pamoic acid moiety shouldmarkedly decrease the pamoate's solubility. Indeed, the most impact onthe dissolution profile of this series of imipramine pamoate derivativeswas observed after reacting other amines with mono-imipramine pamoate.For amorphous mono-imipramine pamoate, FIGS. 82/83, the pH dissolutionprofiles were highly retarded, but with a favorable slow release for thegastric condition. The dose dumping results indicated any presence ofethanol would accelerate release of the active ingredient from the saltform. Interestingly however, only the forty percent ethanol conditionradically altered the active's release after a short time period withabout fifty percent of the active available after thirty minutes. Forthe polymorphic mono-imipramine pamoate, FIGS. 108/109, the pHdissolution profiles were very similar to those found with the amorphoussalt yet the 0.1 N HCl dissolution condition was diminished further. Thepolymorphic mono-imipramine pamoate salt was also found to be lessresponsive to dose dumping than its amorphous counterpart. Thetriethylammonium salt of mono-imipramine pamoate, FIGS. 84/85, exhibiteda similar pH dissolution profile as the free acid, but the twentypercent ethanol condition accelerated release of the active. Still, onlyabout twenty percent of the active was released after thirty minutesunder this condition. Progressing to the Jeffamine® derivative, hereagain it was believed that the salt formation and the hydrophilic natureof the polyoxyalkylene would significantly enhance the dissolutionperformance while having little effect on dose dumping. The findings,FIGS. 88/89, did not support this presumption however; the pHdissolution profile was quite similar to the dissolution propertiesobserved for the free acid and triethylammonium salts. In regard to dosedumping, the presence of ethanol accelerated the active's release fromthe salt, but likely not to the extent to satisfy someone intent onabusing the drug. For the supposed hydrophobic stearylamine derivative,FIGS. 86/87, the pH dissolution profile was highly retarded, andinterestingly, the compound did not respond to ethanol in the dosedumping challenge. Clearly, this set of experiments led to implicationsconcerning pamoate salts and their utility in abuse deterrence. Withthese derivatives, water soluble salt formers, such as triethylamine andJeffamine® acted to retard the dissolution profiles contrary to currentunderstandings and knowledge. Hence, a negative teaching was observed.

To further explore this aspect of dissolution behavior as augmented bycomplex, mixed salts of active ingredients and salt inclusivedissolution profile modifiers, a similar set of analogues was preparedas mentioned earlier. Instead of imipramine, a different pharmacophorewas employed in this case, namely, hydrocodone. Hence, amorphoushydrocodone Jeffamine® pamoate (1:1:1) and amorphous hydrocodonestearylamine pamoate (1:1:1) were prepared and their pH dissolution anddose dumping properties characterized. For amorphous hydrocodoneJeffamine® pamoate (1:1:1) salt, FIGS. 92/93, the pH and dose dumpingdissolution profiles were slow and linear with very little activeingredient released under any condition. For the amorphous hydrocodonestearylamine pamoate (1:1:1) salt, FIGS. 90/91, a retarded, but fasterpH dissolution profile was observed and the presence of forty percentethanol in the dose dumping challenge indicated ethanol could be used toextract the active amine from the salt.

In comparing the effects of incorporating dissolution modifiers withinthe active ingredient/bis-functional organic acid salt to influence bothpH dissolution and dose dumping profiles, the presence of water solubleenhancers attached to the pamoate moiety surprisingly do not function asexpected, and the presence of an oleophilic component attached to thebis-functional moiety, such as stearylamine, yielded highly unexpectedresults. For imipramine stearylamine pamoate (1:1:1), the impact ofstearylamine on dose dumping was profound by essentially stopping anysuggestion of dose dumping. In contrast, for hydrocodone stearylaminepamoate (1:1:1), the stearylamine component accelerates dose dumping,particularly at the forty percent condition. The comparison betweenbis-functional organic acid derivatives and families of activeingredients with respect to their pH and dose dumping dissolutionperformance characteristics indicates a further design criterion. Whenemploying a dissolution modifying agent as part of the bis-functionalsalt, the properties of the active ingredient must be properly matchedwith the dissolution agent in order to design/engineer a specificdissolution response.

To refine this latter observation, the salt-inclusive dissolutionmodifier approach was applied to d-methylphenidate andracemic-methylphenidate. Consequently, amorphous d-methylphenidatetriethylammonium pamoate (1:1:1) and polymorphic racemic-methylphenidatestearylamine pamoate (1:1:1) salts were prepared and evaluated for theirpH and dose dumping dissolution characteristics. As was observed inFIGS. 80/81 the triethylammonium derivative exhibits superiorperformance characteristics. The d-methylphenidate component releasesnicely from the salt at the gastric (0.1 N HCl condition) and isretarded under higher pH conditions. The lack of any significantdissolution under higher pH indicates the active ingredient would provedifficult to extract from the salt form in an effort to abuse the activecomponent of the salt. Similarly, the triethylammonium salt behavesquite well under the dose-dumping dissolution challenge conditions andconsequently, it does not appear to be susceptible to ethanolextraction. In comparison, the analogous stearylamine derivative, FIGS.78/79, exhibits a highly retarded pH dissolution profile and anunfavorable dose dumping result only at the forty percent condition, buteven then only after a significant period (i.e. sixty minutes).

According to the Merck Index, 14^(th) Edition, ©2006, methylphenidatehydrochloride, imipramine hydrochloride and hydrocodone hydrochlorideare each freely soluble in water. Therefore, as the bis-functionalorganic acid salts (or the mixed salt analogues containing asalt-inclusive dissolution modifier) are subjected to the gastriccondition of 0.1 N HCl, it would be reasonably expected thatappreciable, if not complete dissolution, would occur due to in situformation of the hydrochloride salt. Clearly, this does not occur by astraightforward acid/base chemical dissolution mechanism and theaddition of salt-inclusive dissolution modifiers can be employed toaccelerate or retard the pH and dose dumping dissolution profiles. Inthe specific instances herein, particularly with the AD(H)D drugmethylphenidate, preferred embodiments for abuse-deterrent drugsubstance are distributed equally between polymorphic d-methylphenidatepamoate (2:1) salt (FIGS. 34/35) or amorphous d-methylphenidatetriethylammonium pamoate (1:1:1) salt (FIGS. 80/81). Each exemplarprovided a reasonable pH dissolution profile while not exhibiting anyappreciable susceptibility to dose dumping in the presence of ethanol.

A particular aspect of the present invention is the ability to impartdistinct properties to the drug substance. The drug product may have asingle drug substance or a combination of drug substances. In oneembodiment the drug product comprises a drug substance which exhibitsrapid release and a drug substance which exhibits slow release. Inparticular, the drug product can comprise a rapid release drug substanceand a slower release drug substance wherein each drug substance is abusedeterrent. The drug product can be formulated in different commercialpresentations where, for example, one dosage presentation comprises arapid release drug substance and another dosage presentation comprises aslow release drug substance. Alternatively, the drug product maycomprise both the rapid release drug substance and the slow release drugsubstance for administration in a single dose.

The process of administering pharmaceuticals for AD(H)D patientsinvolves the initial procedure for determining effective dose. A medicalprofessional typically makes an initial determination of dose based on aquantitative, or qualitative analysis of the severity of the disorderand physical characteristics of the patient such as weight. A drugproduct is then prescribed wherein the drug product comprises a suitabledrug substance, preferably, in a rapid release form. The severity of thedisorder is then redetermined or the appearance of side effects isdetermined either qualitatively or by quantitative methods such as bloodanalysis for drug substance levels or side effects. If necessary, asubsequent drug product is prescribed, again in a rapid releaseformulation and the redetermination is repeated. This process istypically repeated until the medical professional considers the dose tobe appropriate. Once an appropriate dose is determined, a drug productis prescribed wherein the appropriate drug substance is released with aslow release profile thereby maintaining the drug at the appropriatelevel for an extended period.

In the present invention a drug product can be prescribed andadministered in a manner wherein proper administration provides atherapeutic effect and the function of the API is realized. With adifferent manner of administration (in other words, a non-therapeuticadministration) the API does not enter the bloodstream in an amountsufficient to be active. To be effective the API must be bio-available.For the purposes of the present invention, one method of establishing acompound's bio-availability is by determining the percentage of weightAPI recovered from an aqueous solution at a pH representative of themethod of administration described herein. For the purposes of thepresent invention a compound is considered to be abuse-deterrent when atleast 85 wt % of the compound is recovered from an aqueous solution at apH representative of the method of non-therapeutic administration. If,for example, 85 weight percent or more of a drug compound is recoveredfrom a solution at a pH of 4-9, pH 7 for example, the material isconsidered to be bio-unavailable at a mucosal membrane and is considerednon-permeable at the mucosal membrane and the compound exhibitsprophylactic properties. If, for example, less than 85 weight percent ofa drug compound is recovered from a solution at a pH of less than 4 (pH1 for example), the material is considered to be effective andbio-available under oral administration and is considered permeable in,for example, the gastrointestinal tract due to the release of the API atthe pH of the gastrointestinal tract.

A particularly preferred embodiment and method of administering theamine-containing pharmaceutically active compound is by oral dose. Theoral dose is prepared by first preparing an organic acid addition saltof the active compound. The organic acid addition salt is thenformulated into a dosage presentation to provide an oral dose drugproduct. The formulated product containing the drug substance is alsocomposed of ingredients (excipients) optionally selected from the group,but not limited to, binders, fillers, flow enhancers, surfactants,disintegrants, buffers, and the like; these are typically employed inthe art and found in the “Handbook of Pharmaceutical Excipients”, Rowe,Sheskey and Owen (Editors), Fifth Edition, 2006, Pharmaceutical Press(publishers). When the oral dose is ingested, the organic saltdissociates under physiological conditions. The organic acid portion ofthe amine-containing organic acid addition salt forms the insoluble(organic) acid while the active compound is liberated and becomesbio-available. Efforts to directly isolate the active compound from theoral dose would be thwarted as described herein.

A common technique for de-formulating drug products, particularly forillicit use, is to isolate the active ingredient by organic phaseextraction and separation from an aqueous environment. The technologydisclosed herein interrupts this extraction process.

In an embodiment of the present invention, the controlled substance isan amine-containing organic acid addition salt which does not release inthe pH window of about 4 to about 9. At a pH of less than about 4, thesubject organic salts become protonated with the concomitantprecipitation or gelling of the organic acid. At pH greater than about9, the addition salt is soluble yet it is quite difficult to effectseparation of the organic acid component and the active amine by organicsolvent extraction.

The drug substances of the present invention are prepared by either asequential reaction wherein amines (or amine salts) are addedsequentially to a bis-functional organic acid (or organic acid salt) orby a displacement reaction wherein a bis-functional organic acidderivative is reacted with amines and one amine is displaced therebyforming a mixed amine (salt) compound.

By way of example, the initial reaction is at least one amine containingcompound with a bis-functional organic acid defined by:

wherein Y³ and Y⁴ are carboxylate salts or lower molecular weight estersindependently selected from groups capable of displacement with at leastone of said pharmaceutically active compound and said amine to form thedrug substance salt or mixed salt (when an amine dissolution modifier isemployed);R¹¹² and R¹¹³ are independently selected from hydrogen, alkyl of 1-6carbons, alkylacyl of 1-8 carbons or arylacyl of 7-15 carbons;R¹¹⁴ will replace one of R¹¹⁵, R¹¹⁶, R¹¹⁷ or R¹¹⁸ and one of R¹¹⁹, R¹²⁰,R¹²¹ or R¹²² and is an alkyl or branched alkyl of 1-10 carbons, aryl,arylalkyl of 7-15 carbons and whereinR¹¹⁴ may include at least one optically active carbon; andR¹¹⁵, R¹¹⁶, R¹¹⁷, R¹¹⁸, R¹¹⁹, R¹²⁰, R¹²¹ and R¹²², are independentlyselected from hydrogen, alkyl of 1-6 carbons, and wherein adjacentgroups may be taken together to form a cyclic alkyl or cyclic arylmoiety. In one embodiment the reaction employs about a mole of amine permole of the bis-functional organic acid derivative thereby forming a 1:1conjugate. More preferably, the amine and bis-functional acid are in amolar ratio of about 0.9 to 1.1. In another embodiment an excess ofamine is added, or at least about 2 moles of amine per mole ofbis-functional organic acid, to form a 2:1 compound. In either case asecond amine is added whereby either the second group on thebis-functional organic acid derivative is reacted, for the 1:1conjugate, or a previously reacted amine is displaced. The first amineor second amine can be a pharmaceutically active compound or adissolution modifying amine.

Throughout the specification terms of art such as alkyl, aryl,alkylaryl, cyclic alkyl, cyclic aryl, alkylacyl, arylacyl, benzyl,acetyl and similar terms are intended to refer to unsubstituted orsubstituted moieties.

EXPERIMENTAL METHODS

Differential Scanning Calorimetry (DSC)

Samples were evaluated using a Differential Scanning calorimeter from TAInstruments (DSC 2010). Prior to analysis of samples, a single-pointcalibration of the TA Instruments DSC 2010 Differential Scanningcalorimeter (DSC 2010) with the element indium as calibration standard(156.6±0.25° C.) was completed.

Infrared Spectroscopy (FTIR)

IR Spectra were obtained in a KBr disc using a Perkin Elmer Spectrum BXFourier Transform Infrared Spectrophotometer. For materials existing asoils, spectra were obtained neat (NaCl).

Powder X-Ray Diffraction (PXRD)

Powder X-Ray diffraction patterns were acquired on a Scintag XDS2000powder diffractometer using a copper source and a germanium detector.Polymorphic materials are defined herein as having at least onepolymorph which is distinguishable by powder x-ray diffraction.

HPLC

HPLC analyses were performed on a Waters 2695 HPLC system equipped witha Waters 2996 photo diode array detector.

¹H NMR Spectroscopy

¹H NMR spectra were obtained on at least a 300 MHz Varian Gemini 2000spectrometer. Spectra were referenced to solvent (DMSO-d₆) or totetramethylsilane (TMS; δ=0.00 ppm).

Example 1 Synthesis of Racemic-Methylphenidate Free Base

To a 200 mL beaker was charged 10.0 g (37.1 mmol)racemic-methylphenidate hydrochloride and 135 mL water. About 3.39 g(96.8 mmol) ammonium hydroxide was then added to bring the pH toapproximately 9 upon which an oily semi-solid formed. The product wasextracted with three 100 mL portions of ethyl acetate, the combinedorganic layers dried over sodium sulfate, filtered and concentratedunder reduced pressure at about 40° C. to provide 8.2 g of a clear,colorless viscous oil (95% yield). The IR spectrum of the oil wasconsistent with the intended product.

Example 2 Synthesis of Amorphous Racemic-Methylphenidate Pamoate, (2:1)Salt

To a 100 mL round bottom flask equipped with a magnetic stir bar,thermowell and nitrogen inlet was charged about 1.65 g (3.7 mmol)disodium pamoate (3.2% moisture) and 25 mL water. The pH was adjusted to9-9.5 (pH paper) using 0.1 N sodium hydroxide. A solution of 2.0 g (7.4mmol) racemic-methylphenidate hydrochloride in 37 mL water was prepared(pH 4-4.5 (pH paper)) and added to the above disodium pamoate solutionover three minutes. As the resulting solution became a thick slurry; 20mL more water was added and stirred at ambient temperature for 1.5hours. The solids were collected by filtration (medium fritted glassfilter) and dried under vacuum overnight at ambient temperature toprovide 2.81 g (89%) of an off-white solid (1.42% water) which wasanalyzed by DSC, FTIR (FIG. 2), and PXRD (FIG. 3). PXRD analysisindicated the drug substance to be amorphous and HPLC analysis indicateda 1.8/1 ratio of methylphenidate/pamoate. The NMR results wereconsistent with the assigned structure. The DSC is provided in FIG. 1wherein an endothermic phase change of at least 70 J/gram is observed atgreater than 200° C.

Example 3 Synthesis of Polymorphic Racemic-Methylphenidate Pamoate,(2:1) Salt

To a 100 mL one neck round bottom flask equipped with a magnetic stirbar, thermowell and nitrogen inlet was charged 2.20 g (9.43 mmol)racemic-methylphenidate. As solvent, 17 mL dimethylformamide (DMF) wasthen added which produced a clear colorless solution. Pamoic acid (1.83g; 4.71 mmol; 0.36% moisture) was subsequently added over thirty secondswhich produced a clear yellow solution. The solution was stirred undernitrogen for 3 hours at ambient temperature followed by filtrationthrough a medium fritted glass filter to remove any particulates. Thefiltrate was transferred to a 250 mL one-neck round bottom flask and 54g isopropanol was added over one minute. The solution was concentratedunder reduced pressure at 100° C. to yield 4.2 g of a residue which wassubsequently triturated in 24 g isopropanol and the yellow solidscollected by filtration (medium fritted glass filter). The product wasdried overnight under vacuum at ambient temperature to provide 3.7 g(92%) of a yellow solid (0.36% water) which was analyzed by DSC, FTIR(FIG. 5), and PXRD (FIG. 6). An HPLC analysis indicated a 1.8/1 ratio ofmethylphenidate/pamoate which was corroborated by NMR. The PXRD analysisindicated the drug substance salt was crystalline. The DSC is providedin FIG. 4 wherein an endotherm of at least 75 J/gram is illustratedabove 200° C.

Example 4 Synthesis of Polymorphic Racemic-Methylphenidate Xinafoate

To a 100 mL round bottom flask equipped with a magnetic stir bar,thermowell and nitrogen inlet was charged 1.39 g (7.4 mmol) BON acid(beta-oxy-naphthoic acid) and 13 mL water. Solid sodium hydroxide (0.296g; 7.4 mmol) was added and the solution heated to 50° C. to dissolve allsolids. After cooling to ambient temperature, the pH was adjusted to 9.5with 0.1 N sodium hydroxide. A solution of 2.0 g (7.4 mmol)racemic-methylphenidate hydrochloride in 37 mL water was prepared (pH4-4.5; pH paper) and added to the above BON acid solution at ambienttemperature upon which a sticky gum formed. More water was added (20 mL)to facilitate stirring. The aqueous mixture was carefully decanted awayfrom the gum, more water added to the residue, the mixture stirred for 5minutes, again the water decanted away from the gum, and the residuedried under vacuum to provide 1.5 g (48%) of a tan crunchy solid (2.09%moisture) which was analyzed by DSC, FTIR (FIG. 8), and PXRD (FIG. 9).HPLC analysis confirmed the 1:1 stoichiometric relationship betweenmethylphenidate and the BON acid moiety (xinafoate) and PXRD indicatedthe product to be crystalline. The DSC is provided in FIG. 7 wherein anendotherm of at least 75 J/gram is illustrated above 155° C.

Example 5 Synthesis of d-Methylphenidate Free Base

To a 200 mL beaker was charged 10.0 g (37.1 mmol)racemic-methylphenidate hydrochloride and 135 mL water. Ammoniumhydroxide (3.40 g; 96.8 mmol) was then added to bring the pH toapproximately 9 upon which an oily semi-solid formed. The product wasextracted with three 100 mL portions of ethyl acetate, the combinedorganic layers were dried over sodium sulfate, filtered and concentratedunder reduce pressure at 40° C. to provide 8.5 g of a clear, colorlessviscous oil (98% yield). The free base was characterized by FTIR andfound to be consistent with the anticipated structure

Example 6 Synthesis of Amorphous d-Methylphenidate Pamoate, (2:1) Salt

To a 250 mL round bottom flask equipped with a magnetic stir bar,thermowell and nitrogen inlet was charged 1.65 g (3.7 mmol) disodiumpamoate (3.16% moisture) and 22 mL water. The pH of the solution wasadjusted to 9-9.5 (pH paper) with 0.1 N sodium hydroxide. A solution of2.0 g (7.4 mmol) d-methylphenidate hydrochloride in 37 mL water wasprepared (pH 4-4.5; pH paper) and added over two minutes to the disodiumpamoate solution. As the resulting mixture became a thick slurry; 37 mLmore water was added and stirring continued overnight at ambienttemperature. The solids were collected by filtration (medium frittedglass filter) and dried under vacuum overnight at ambient temperature toprovide 2.7 g (85%) of an off-white solid (1.44% water) which wasanalyzed by DSC (FIG. 10), FTIR (FIG. 11), and PXRD (FIG. 12). PXRDanalysis confirmed the product to be amorphous. HPLC analysis indicateda 1.9/1 ratio of d-methylphenidate/pamoate. The DSC is provided in FIG.10 wherein an endothermic phase change of at least 45 J/gram is observedat greater than 70° C. and an endothermic phase change of at least 30J/gram at greater than 180° C. is observed.

Example 7 Synthesis of Polymorphic d-Methylphenidate Pamoate, (2:1) Salt

To a 100 mL round bottom flask equipped with a magnetic stir bar,thermowell and nitrogen inlet was charged 0.41 g (0.925 mmol) disodiumpamoate (3.16% moisture) and 10 mL water. A solution of 0.5 g (1.85mmol) d-methylphenidate hydrochloride in 10 mL water was prepared andadded to the above disodium pamoate solution over a thirty minute periodunder a nitrogen atmosphere. The solution was then heated from ambienttemperature to 95° C. and held on temperature for 5 hours under nitrogenupon which the solids turned to a yellow gum. Heating was ceased and themixture allowed to slowly cool back to ambient temperature overnight andcontinuously under a nitrogen atmosphere. The solids were collected byfiltration (medium fritted glass filter) and dried overnight undervacuum at ambient temperature to provide 0.7 g (89%) of a yellow solid(0.51% water) which was analyzed by DSC, HPLC, FTIR (FIG. 14), and PXRD(FIG. 15). PXRD showed the product to be crystalline. HPLC showed a1.7/1 ratio of d-methylphenidate/pamoate. The DSC is provided in FIG. 13wherein an endothermic phase change of at least 35 J/gram is observed atgreater than 185° C.

Example 8 Synthesis of Amorphous d-Methylphenidate Xinafoate

To a 100 mL round bottom flask equipped with a magnetic stir bar,thermowell and nitrogen inlet was charged 0.695 g (3.7 mmol) BON Acid(beta-oxy-naphthoic acid) and 10 mL water. Solid sodium hydroxide (0.148g; 3.7 mmol) was added and the solution heated to 50° C. to dissolve allsolids. After cooling to ambient temperature, the pH was adjusted to9-9.5 with 0.1 N sodium hydroxide. A solution of 1.0 g (3.7 mmol)d-methylphenidate hydrochloride in 20 mL water was prepared (pH 4-4.5)and added to the above BON Acid solution at ambient temperature over 15minutes upon which a sticky gum formed. The mixture was heated to 95° C.for 3 hours under a nitrogen atmosphere with oil formation apparent.After the hold period, the mixture was cooled to ambient temperature andthe aqueous liquid was carefully decanted from the gum. More water addedto the gum, stirring continued for 5 minutes, and again, the mixture wasdecanted. The residual gum was dried under vacuum to provide 1.0 g (64%)of a light yellow solid which was mostly brittle yet retained a smallportion of the gummy solid, (2.8% moisture). The solid was analyzed byDSC, HPLC, FTIR (FIG. 17), and PXRD (FIG. 18). The PXRD analysisconfirmed the drug substance was amorphous and an HPLC analysisconfirmed the 1:1 stoichiometric relationship of d-methylphenidate andxinafoate moiety. The DSC is provided in FIG. 16 wherein an endothermicphase change of at least 10 J/gram is observed at greater than 45° C.and an endothermic phase change of at least 50 J/gram at greater than160° C. is observed.

Example 9 Synthesis of Dextro-Amphetamine Free Base

To a 200 mL beaker equipped with a magnetic stir bar was charged 5.0 g(13.6 mmol) dextro-amphetamine sulfate and 50 mL water to dissolve thesolid. Ammonium hydroxide (2.5 g; 70.7 mmol) was then added and thesolution remained clear and colorless. The solution was subsequentlyextracted with three 50 mL portions of ethyl acetate and the combinedorganic layers were dried over sodium sulfate, filtered and concentratedunder vacuum at 50° C. to provide 3.4 g (92%) of a clear colorless oil.The FTIR spectrum of the free base was consistent with the intendedstructure.

Example 10 Synthesis of Amorphous Dextro-Amphetamine Pamoate, (2:1) Salt

To a 10 mL round bottom flask equipped with a magnetic stir bar,thermowell and nitrogen inlet was charged 1.65 g (3.7 mmol) disodiumpamoate (3.16% moisture) and 22 mL water. The pH was adjusted to 9-9.5with 0.4 g of 0.1 N sodium hydroxide. A solution of dextro-amphetaminehydrochloride in water was prepared (pH 4-4.5) by mixing 1.0 g (7.4mmol) dextro-amphetamine (free base from Example 9), 2.3 mL water and 1equivalent (about 7.4 mL of 1N hydrochloric acid) to achieve a pH ofabout 4. The dextro-amphetamine hydrochloride solution was added to theabove disodium pamoate solution over one minute under a slow stream ofnitrogen. Solids formed initially but then turned to an intractablesticky gum. The aqueous mixture was carefully decanted, more water addedto the residual gum, and stirring resumed for 5 minutes. The water wasagain decanted and the residual gum dried under vacuum to provide 1.6 g(67%) of a shiny tan crunchy solid (2.8% water) which was analyzed byDSC, HPLC, FTIR (FIG. 20), and PXRD (FIG. 21). PXRD analysis indicatedthe drug substance to be amorphous. HPLC analysis indicated a 1.7/1ratio of dextro-amphetamine/pamoate. The DSC is provided in FIG. 19wherein an endothermic phase change of at least 10 J/gram is observed atgreater than 200° C. and an endothermic phase change of at least 75J/gram at greater than 220° C. is observed.

Example 11 Synthesis of Polymorphic Dextro-Amphetamine Pamoate, (2:1)Salt

To a 100 mL round bottom flask equipped with a magnetic stir bar,thermowell and nitrogen inlet was charged 3.32 g (7.74 mmol) disodiumpamoate and 40 mL water. A solution of dextro-amphetamine hydrochloridein 40 mL water was prepared in situ by mixing 2.0 g (14.8 mmol)dextro-amphetamine free base, with the water charge and 1 equivalent(14.8 mL) hydrochloric acid (1 N). The dextro-amphetamine hydrochloridewas subsequently added to the above disodium pamoate solution over 40minutes under a slow stream of nitrogen. Free-flowing solids formed uponaddition but then later turned to a partial gum. The solution was thenheated from ambient temperature to about 46° C. over 50 minutes, then to70° C. over the next 20 minutes and finally to 88-92° C. over the next30 minutes and held at this temperature for an additional 2 hours undernitrogen upon which the solids turned to a yellow gummy solid. Heatingwas ceased and the mixture allowed to slowly cool to ambient temperatureover the next 1.5 hours while remaining under a nitrogen atmosphere.Upon cooling, the solid became free flowing and were collected byfiltration through a medium fritted funnel, washed with a small portionof water and dried under vacuum to provide 4.38 g (90%) of a yellowsolid (0.29% water) which was analyzed by DSC, FTIR (FIG. 23), and PXRD(FIG. 24). The PXRD diffractogram was consistent with a drug substancehaving polymorphic character. The HPLC chromatogram indicated a 1.8/1ratio of dextro-amphetamine/pamoate. The DSC is provided in FIG. 22wherein an endothermic phase change of at least 60 J/gram is observed atgreater than 200° C.

Example 12 Synthesis of Polymorphic Dextro-Amphetamine Xinafoate

To a 100 mL round bottom flask equipped with a magnetic stir bar,thermowell and nitrogen inlet was charged 1.39 g (7.4 mmol) BON Acid(beta-oxy-naphthoic acid) and 13 mL water. Solid sodium hydroxide (0.296g; 7.4 mmol) was added and the solution heated to 50° C. to dissolve allsolids. After cooling to ambient temperature, the pH was adjusted to9-9.5 with 0.1 N sodium hydroxide. A solution of dextro-amphetaminehydrochloride in water was prepared by mixing 1.0 g (7.4 mmol)dextro-amphetamine free base, 20 mL water and 1 equivalent (about 7.4mL) hydrochloric acid (1 N). The dextro-amphetamine hydrochloride wasadded to the above disodium pamoate solution over 5 minutes under a slowstream of nitrogen with a sticky gum initially forming. The solution wasstirred for 1 hour during which time the gum turned to a solid. Thesolids were collected by filtration (medium fritted glass filter),washed with water and dried overnight under vacuum at ambienttemperature to provide 1.3 g (54%) of a light-yellow solid (0.06% water)which was analyzed by DSC, FTIR (FIG. 26), and PXRD (FIG. 27). The PXRDdiffractogram indicated the polymorphic character of the isolated drugsubstance. The HPLC chromatogram indicated the 1:1 stoichiometricrelationship of dextro-amphetamine and BON Acid (xinafoate) components.The DSC is provided in FIG. 25 wherein an endothermic phase change of atleast 60 J/gram is observed at greater than 125° C.

Example 13 Synthesis of Polymorphic Racemic-Methylphenidate StearylaminePamoate, (1:1:1) Salt

To a 100 mL round-bottom flask equipped with a magnetic stir bar andaddition funnel was charged 0.8 g (0.936 mmol) methylphenidate pamoate,(2:1) salt and 20 g toluene to form a suspension. A solution of 252.3 mg(0.936 mmol) octadecylamine in 20 g toluene was prepared and addeddropwise to the above suspension over 30 minutes. The suspension wasstirred overnight and the solids collected by filtration through amedium fritted filter. The product was dried under vacuum to provide 700mg (84%) of an off-white solid (2.0% water) which was characterized byDSC, FTIR (FIG. 47), PXRD (FIG. 48), ¹H NMR (FIG. 49), and HPLC. ThePXRD diffractogram indicated the drug substance to be crystalline. Therelative ratio of methylphenidate/pamoate was determined to be 0.9/1 byHPLC and the structure corroborated by ¹H NMR with the relative ratio ofstearylamine/pamoate as ˜1/1. The filtrate from the above work-up wasconcentrated at reduced pressure and dried under vacuum to give 220 mgof a yellow residue which was by FTIR consistent with authenticmethylphenidate free base. The DSC scan is provided in FIG. 46 whereinillustrated is an endothermic phase change of at least 15 J/g at atemperature above 50° C.; an endothermic phase change of at least 10 J/gat a temperature of above 90° C.; an endothermic phase change of atleast 2 J/g at a temperature above 105° C.; an endothermic phase changeof at least 4 J/g at above 155° C. and an endothermic phase change of atleast 20 J/g above 180° C.

Example 14 Synthesis of Amorphous d-MethylphenidateMono-Triethylammonium Pamoate, (1:1:1) Salt

To a 100 mL round-bottom flask equipped with a magnetic stir bar andaddition funnel was charged 722.1 mg (1.85 mmol) pamoic acid, 20 mLwater and 423.0 mg (4.18 mmol) triethylamine. A solution of 0.5 g (1.85mmol) d-methylphenidate hydrochloride in 20 mL water was added to theabove solution over 3 hours with formation of a gum.

The water was carefully decanted and the residual gum dried under vacuumto provide 0.9 g (67%) of a tan solid (3.47% water) which wascharacterized by DSC, FTIR (FIG. 51), PXRD (FIG. 52), ¹H NMR (FIG. 53),and HPLC. The PXRD diffractogram indicated the isolated drug substancewas amorphous. The relative ratio of d-methylphenidate to pamoate wasdetermined to be 1.0/1 by HPLC analysis and further corroborated by therelative ratio of triethylammonium ion to pamoate moiety as ˜1/1 asdetermined by ¹H NMR. The DSC is provided in FIG. 50 wherein illustratedis an endothermic phase change of at least 12 J/g at a temperature above240° C.

Example 15 Synthesis of Amorphous Imipramine Pamoate, 1:1 Salt

To a 500 mL round bottom flask equipped with a magnetic stir bar wascharged 3.0 g (3.9 mmol) imipramine pamoate mono-triethylammonium salt(as was prepared in Example 16) and 90 g acetone to produce a cloudyyellow solution. Hydrochloric acid solution (1.1 equivalents, 0.1 N HCl;42.6 mL) was subsequently added at once to the solution and the combinedmixture stirred for an additional 30 minutes whereupon the solutiongradually became progressively cloudier. The solution was filteredthrough a medium fritted filter (removing ˜80 mg of yellow pamoic acid)and the resulting clear filtrate was concentrated under reduce pressureat 40° C. until all volatile solvent was removed leaving solids and anaqueous layer. The water was carefully decanted and the solids washedwith more water and again, the water was decanted. The remaining solidswere slurried in acetone (50 g) and more pamoic acid (−0.4 g) wascollected by filtration. The slightly turbid filtrate was refilteredagain to provide a clear yellow solution which was concentrated underreduce pressure at 40° C. to remove ˜90% of the acetone. The resultingturbid solution was filtered one more time as above and the clearsolution again quickly concentrated under reduced pressure at 40° C. Theresulting solids were dried under vacuum to provide 1.57 g (60%) of atan yellow solid (2.0% water) which was characterized by DSC (FIG. 54),FTIR (FIG. 55), PXRD (FIG. 56)¹H NMR (FIG. 57), and HPLC. The PXRDdiffractogram indicated the material was amorphous. The HPLCchromatogram and ¹H NMR spectrum were both consistent with thestoichiometric ratio for the drug substance as ˜1/1 imipramine/pamoate.¹H NMR also showed approximately 0.47 equivalents acetone included inthe material.

Example 16 Synthesis of Amorphous Imipramine PamoateMono-Triethylammonium, (1:1:1) Salt

Method A

To a one liter round-bottom flask equipped with a magnetic stir bar andaddition funnel was charged 9.0 g (15.2 mmol) di-triethylammoniumpamoate and 192 mL water. The solution was stirred for 5 minutes andthen a pre-made solution of 4.83 g (15.2 mmol) imipramine hydrochloridein 93 mL water was added dropwise over 2.75 hours to the abovedi-triethylammonium pamoate solution. After the addition was complete,the solution was stirred for an additional hour. The water was carefullydecanted from the solid/gum that formed and a small aliquot of wateradded to the residue, which was subsequently collected by filtration,washed with water and dried under vacuum to provide 9.18 g (78%) of anoff-white solid (2.2% water). The product was characterized by DSC (FIG.58), FTIR (FIG. 59), PXRD (FIG. 60), ¹H NMR (FIG. 61) and HPLC. The PXRDdiffractogram indicated the isolated drug substance was amorphous. Therelative ratio of imipramine to pamoate was determined to be 1.3/1 byHPLC and the ratio corroborated by ¹H NMR. The relative ratio oftriethylammonium ion to pamoate moiety was approximately 1/1 by ¹H NMR.

Method B

To a 100 mL round-bottom flask equipped with a magnetic stir bar andaddition funnel was charged 1.23 g (3.16 mmol) pamoic acid, 40 mL waterand 769.0 mg (7.6 mmol) triethylamine. A solution of 1.0 g (3.16 mmol)imipramine hydrochloride in 20 mL water was added to the above solutionover 3 hours with gum formation. The water was carefully decanted andthe gum dried under vacuum to provide 2.1 g (86%) of a tan solid (2.24%water). The relative ratio of imipramine to pamoate was determined to be1.1/1 by HPLC (and corroborated by ¹H NMR). The relative ratio oftriethylammonium ion to pamoate was ˜1/1 by ¹H NMR.

Example 17 Synthesis of Polymorphic Imipramine Stearylamine Pamoate,(1:1:1) Salt

To a 100 mL round-bottom flask equipped with a magnetic stir bar andaddition funnel was charged 730 mg (0.769 mmol) imipramine pamoate,(2:1) salt (prepared as described in King, et al.) in 10.7 g toluene toform a suspension. A solution of 207.3 mg (0.769 mmol) octadecylamine in12.5 g toluene was prepared and added dropwise to the above suspensionover 1 hour. The suspension was stirred for an additional 3 hours andthe solids collected by filtration through a medium fritted filter. Theproduct was dried under vacuum to provide 600 mg (83%) of a white solid(2.5% water) which was characterized by DSC, FTIR (FIG. 63), PXRD (FIG.64), ¹H NMR (FIG. 65) and HPLC. The PXRD diffractogram indicated theisolated drug product was crystalline. The relative ratio ofimipramine/pamoate was determined to be 1.2/1 by HPLC (and corroboratedby ¹H NMR). The relative ratio of stearylamine/pamoate was determined tobe about 1/1 by ¹H NMR. The filtrate from the above work-up wasconcentrated under reduced pressure and dried under vacuum to give 200mg of a yellow oil which was characterized by FTIR and ¹H NMR. Theanalyses were consistent with those obtained for imipramine free basedescribed in U.S. Pat. No. 5,578,500. The DSC thermogram is provided inFIG. 62 wherein an endothermic phase change of at least 40 J/g isobserved at a temperature above 70° C. and an endothermic phase changeof at least 1 J/g is observed above 125° C.

Example 18 Synthesis of Amorphous Imipramine Jeffamine® Pamoate, (1:1:1)Salt

To a 500 mL round-bottom flask equipped with a magnetic stir bar andaddition funnel was charged 6.82 g (7.18 mmol) imipramine pamoate (2:1)(prepared as described in U.S. Pat. No. 7,718,649 [King et al.] and 135g toluene to form a suspension. A solution consisting of 4.31 g (7.18mmol) Jeffamine XTJ-505® available from Huntsman Chemical Company and 91g toluene was added dropwise to the above suspension over 30 minutes.The contents were allowed to stir overnight at ambient temperature.Solids were collected from the mixture by filtration through a mediumfritted filter and dried under vacuum to provide 3.42 g of a lightyellow solid which was characterized by DSC, FTIR, ¹H NMR and HPLC whichconfirmed the solids consisted of imipramine pamoate (2:1) salt. Thetoluene filtrate was charged to a one liter round-bottom flask with amagnetic stir bar and to the solution was added 260 mL water and thecontents gently mixed but not too vigorously as to avoid forming anemulsion. The two layers were transferred to a separatory funnel andallowed phase with the layers also containing some oil droplets whichwere not very soluble in either layer. The layers were separated leavingthe oily residue behind in the separatory funnel. Concentration of theaqueous layer under reduced pressure at 70° C. followed by dryingprovided 2.46 g of a yellow oil which was characterized by FTIR, ¹H NMRand HPLC which was shown to be Jeffamine® pamoate (2:1) salt.Concentration of the toluene layer under reduced pressure at 70° C.followed by drying provided 4.36 g of a semi-solid and from whichdecanting provided a yellow oil was isolated. The decanted yellow oil(3.39 g) was shown by FTIR and HPLC to be a mixture of mostly imipraminebase along with some Jeffamine® pamoate, (2:1) salt. The yellow solidremaining was triturated in toluene and washed with water and driedunder vacuum to provide 1.17 g of a soft yellow gum which wascharacterized by DSC, IR and HPLC and which was found to be 1:1:1imipramine Jeffamine® pamoate (impure when compared with pure 1:1:1imipramine Jeffamine® pamoate isolated below) along with some excessimipramine. The oily residue left behind in the separatory funnel abovewas washed with two portions of toluene and after decanting, theresulting residue dissolved in acetone, transferred to a round-bottomflask and concentrated under reduced pressure at 50° C. The semi-solidobtained was washed by decanting with two portions of water and theresulting extract concentrated under reduced pressure at 70° C. to yielda thick viscous oil which was then dried under vacuum to provide 0.98 gof a light yellow sticky solid (11% yield; 1.0% moisture). The drugsubstance was characterized by DSC, FTIR (FIG. 67), PXRD (FIG. 68), ¹HNMR (FIG. 69), and HPLC. The PXRD diffractogram confirmed the drugsubstance was amorphous. The relative ratio of imipramine/pamoate wasdetermined to be 1.3/1 by HPLC and corroborated by ¹H NMR. The relativeratio of Jeffamine®/pamoate was determined to be ˜1/1 by ¹H NMR. The DSCthermogram is provided in FIG. 66 wherein observed is an endothermicphase change of at least 50 J/g at a temperature above 240° C.

Example 19 Synthesis of Amorphous Hydrocodone Stearylamine Pamoate,(1:1:1) Salt

To a 100 mL round-bottom flask equipped with a magnetic stir bar andaddition funnel was charged 660.0 mg (0.669 mmol) hydrocodone pamoate,(2:1) prepared by the procedure in co-pending patent application,application Ser. No. 12/423,641 entitled, Opioid Salts and FormulationExhibiting Anti-Abuse and Anti-Dose Dumping Properties, King et al., and10.0 g toluene to form a suspension. A solution of 180.3 mg (0.669 mmol)octadecylamine in 10.0 g toluene was prepared and added dropwise to theabove suspension over a 20 minute period. The suspension was stirredovernight and the solids collected by filtration through a mediumfritted filter. The drug substance was dried under vacuum to provide 580mg (91%) of an off-white solid (4.1% water) which was characterized byDSC, FTIR (FIG. 71), PXRD (FIG. 72), ¹H NMR (FIG. 73), and HPLC. ThePXRD diffractogram indicated the drug substance was predominantlyamorphous. The relative ratio of hydrocodone/pamoate was determined tobe 1.1/1 by HPLC analysis and was corroborated by ¹H NMR. The relativeratio of stearylamine/pamoate was determined to be ˜1/1 by ¹H NMR. TheDSC thermogram is provided in FIG. 70 wherein an endothermic phasechange of at least 1 J/g at a temperature above 65° C.; an endothermicphase change of at least 1 J/g above 70° C. and an endothermic phasechange of at least 3 J/g above 105° C. is observed.

The filtrate from the above work-up was concentrated under reducepressure and dried under vacuum to give ˜200 mg of an off-white solidwhich was characterized by DSC, melting point and IR, and found to matchauthentic hydrocodone free base.

Example 20 Synthesis of Amorphous Hydrocodone Jeffamine® Pamoate,(1:1:1) Salt

To a 250 mL round-bottom flask equipped with a magnetic stir bar andaddition funnel was charged 3.00 g (3.04 mmol) hydrocodone pamoate,(2:1) salt as used in Example 19, and 50 g toluene to form a suspension.A solution consisting of 1.82 g (3.04 mmol) Jeffamine XTJ-505® availableform Huntsman Chemical Company, and 50 g/toluene was prepared separatelyand added dropwise to the above suspension over 38 minutes. The contentswere allowed to stir overnight. Solids were collected through a mediumfritted filter and dried under vacuum to provide 2.6 g (67%) of a lightyellow solid (0.6% water) which was characterized by DSC, FTIR (FIG.75), PXRD (FIG. 76), ¹H NMR (FIG. 77), and HPLC. The PXRD diffractogramindicated the drug substance was amorphous. HPLC analysis indicated thedrug substance contained a ratio of 1.4/1 hydrocodone/pamoate. ProtonNMR corroborated the relative ratio of hydrocodone/pamoate to be˜1.3-1.4/1 and the relative ratio of Jeffamine®/pamoate to be˜0.6-0.7/1. The DSC thermogram is provided in FIG. 74 whereinillustrated is an endothermic phase change of at least 5 J/g at atemperature above 105° C. and an endothermic phase change of at least 1J/g at a temperature above 150° C.

After the above filtration, the toluene filtrate was charged to a oneliter round-bottom flask with a magnetic stir bar and to the solutionwas added 120 mL water and the contents gently mixed to avoid forming anemulsion. The two layers were transferred to a separatory funnel andallowed to phase into two layers and the layers separated.

Concentration of the aqueous layer under reduce pressure at 70° C.followed by drying provided 0.72 g of a yellow oil which wascharacterized by FTIR, ¹H NMR and HPLC indicating the isolation of 0.6/1hydrocodone pamoate salt. The ¹H NMR spectrum indicated a small amountof hydrocodone relative to pamoate and the presence of excessJeffamine®.

Concentration of the toluene layer under reduced pressure at 70° C.followed by drying provided 1.36 g of a soft yellow residue which wascharacterized by DSC, FTIR, PXRD and HPLC which collectively indicatedthe residue to consists of 22.4/1 hydrocodone pamoate salt, e.g. anexcess of hydrocodone base. The ¹H NMR spectrum of the toluene extractindicated a large excess of hydrocodone and Jeffamine® and the presenceof very little pamoate moiety.

Example 21 Synthesis of Amorphous Bis(Triethylammonium) Pamoate

To a one liter round-bottom flask equipped with a magnetic stir bar wascharged 20.0 g (51.2 mmol) pamoic acid (0.5% moisture) and 640 mL water.To this suspension was added 11.2 g (110.1 mmol) triethylamine over aperiod of about 30 seconds which produced a solution with a pH about8.5-9. The solution was stirred for approximately 1 hour and filtered toremove any particulates. The clear filtrate was concentrated underreduced pressure at 85° C. and dried (under vacuum overnight to provide29.82 g (99%) of a tan to light brown solid (1.46% moisture) which wascharacterized by DSC (FIG. 94), FTIR (FIG. 95) PXRD (FIG. 96), and ¹HNMR (FIG. 97). The results were consistent with the assigned structureand the PXRD diffractogram indicated the material was amorphous.

Example 22 Synthesis of Tetronic® Pamoate, 1:1 Salt

To a 100 mL beaker equipped with a magnetic stir bar was charged 9.98 g(2.77 mmol) Tetronic 701® and 18.7 g water which formed a cloudymixture. Two equivalents of HCl (relative to Tetronic 701®) weredelivered via addition of 5.54 mL 1N hydrochloric acid and stirred forten minutes upon which the solution became clear.

To a 100 mL round-bottom flask equipped with a magnetic stir bar,thermowell and addition funnel were charged 1.20 g (2.77 mmol) disodiumpamoate in 15 g water and the pH adjusted to about 9.5 with a smallquantity of 1N sodium hydroxide solution. The Tetronic 701® solutionprepared above was added to the disodium pamoate solution via additionfunnel over about forty minutes upon which the solution became turbid.The solution was stirred for two hours and was subsequently extractedwith diethyl ether (111 g, 1^(st) portion; 61 g, 2^(nd) extraction). Thecombined organic layers were concentrated under reduced pressure atambient temperature to provide 10.5 g of a clear viscous yellow oil (95%yield) which was characterized by IR and proton NMR.

Example 23 Synthesis of Polymorphic Imipramine Pamoate, 1:1 Salt

To a 100 mL round bottom flask equipped with a magnetic stir bar,thermowell, nitrogen inlet and condenser was charged 397.7 mg (0.419mmol) imipramine pamoate, Form II (2:1) prepared according to King etal. U.S. Pat. No. 7,718,649, 1.67 g (0.419 mmol) Tetronic 701® pamoate(prepared as described above) and about 27.9 g toluene to produce acloudy yellow suspension. The mixture was heated to about 37-40° C.under nitrogen and stirred overnight at this temperature. The mixturewas allowed to cool to ambient temperature, collected by filtrationthrough a medium fritted filter, washed with a small portion of tolueneand dried to provide 0.52 g (93%) of a pale yellow-off-white solid(0.277% moisture content) which was characterized by DSC, FTIR (FIG.105), PXRD (FIG. 106) and ¹H NMR (FIG. 107). The PXRD analysis indicatedisolation of a polymorphic, crystalline material. The relative ratio ofimipramine/pamoate was determined to be about 1/1 by HPLC analysis andthrough structure elucidation by ¹H NMR. The DSC thermogram is providedin FIG. 104 wherein illustrated is an endothermic phase change of atleast 60 J/g at a temperature above 200° C.

The filtrate from above was evaporated to provide about 1.43 g of ayellow oil which was characterized and identified by ¹H NMR and FTIR tobe consistent with Tetronic 701®.

Example 24 Dissolution Procedure

The amine containing organic acid addition salts of the presentinvention were tested to determine their dissolution profile as afunction of pH, and as a function of ethanol concentration in acidicmedia (dose dumping). To perform these experiments the buffereddissolution media and acidic ethanol solutions were prepared asidentified herein, “Preparation of Solutions”. The test procedure wasderived from the procedures cited in the United States Pharmacopeia andNational Formulary (USP), numbers <1087> and <711>. The dose dumpingprocedure was adopted from the United States Food and DrugAdministration's guidance regarding the dose dumping of oxymorphone. Thesampling interval and regimen were defined and each sample analyzed byHPLC. Results from the HPLC analyses were plotted as a function of timeand dissolution condition (FIG. 28-45, FIGS. 78-93, and FIGS. 98-103).This procedure was used to obtain the pH and dose dumping dissolutionprofiles disclosed herein. Verb tense within the procedure descriptiondoes not indicate a prospective condition but was used to facilitate themethod's description herein. All activities within the procedure wereconducted and executed for each of the compounds reported herein.

Dissolution Procedure

The following is a general procedure for intrinsic dissolutionexperiments.

Preparation of Solutions:

All reagents are ACS grade or equivalent. All solvents used are aminimal of HPLC grade. Water used in the preparations of all solutionsis USP grade. These solution preparations have been taken directly fromthe USP.

Preparation of 0.1 N HCl:

To prepare 4 L of solution, add 33.3 mL of concentrated HCl to 977.7 mLof water, then add an additional 3000 mL of water.

Preparation of pH 4.5 Acetate Buffer:

To prepare 1 L of solution add 2.99 g of sodium acetate tri-hydrate(NaC₂H₃O₂.3H₂O) to a 1000 mL volumetric flask, then add 14.0 mLs of 2Nacetic acid solution. Dissolve and dilute to volume with water.

Preparation of pH 6.8 Phosphate Buffer:

To prepare 200 mL of solution first prepare a 0.2 M potassium phosphatesolution by adding 27.22 g of monobasic potassium phosphate (KH₂PO₄) toa 1000 mL volumetric flask, then dissolve and dilute to volume withwater. Add 50 mL of this solution to a 200 mL volumetric flask, then add22.4 mL of 0.2M NaOH and dilute to volume with water.

Preparation of 5% Ethanol Solution for Dose Dumping DissolutionProfiles:

To prepare 900 mL of media combine 45 mL of 200 proof ethanol with 855mL of 0.1 N HCl (see preparation procedure above).

Preparation of 20% Ethanol Solution for Dose Dumping DissolutionProfiles:

To prepare 900 mL of media combine 180 mL of 200 proof ethanol with 720mL of 0.1 N HCl (see preparation procedure above).

Preparation of 40% Ethanol Solution for Dose Dumping DissolutionProfiles:

To prepare 900 mL of media combine 360 mL of 200 proof ethanol with 540mL of 0.1 N HCl (see preparation procedure above).

Preparation of Mobile Phase A (0.1% TFA in H₂O):

To prepare 1 L of mobile phase, add 1.0 mL of TFA to 1000 mL of H₂O. Mixwell and filter this solution through a 0.45 μM nylon filter.

Preparation of Mobile Phase B (0.1% TFA in Acetonitrile):

To prepare 1 L of mobile phase, add 1.0 mL of TFA to 1000 mLacetonitrile. Mix well and filter this solution through a 0.45 μM nylonfilter.

Preparation of Mobile Needle/Seal Wash Solution:

To prepare 1 L of solution, add 500 mL H₂O to 500 mL acetonitrile andmix well.

Procedure:

Intrinsic Dissolution Profiles:

Note: The following procedures were derived from USP <1087> IntrinsicDissolution and USP <711> Dissolution methods, as well as manufacturerrecommended procedures for use of the International CrystalsLaboratories intrinsic dissolution disks.

Preparation of API Pellet for Intrinsic Dissolution:

The material which is to be subjected to dissolution is weighed using ananalytical balance. 45.00-55.00 mgs of the analyte was weighed andtransferred to an International Crystals Laboratories fixed/static disk316 stainless die with a 0.8 cm diameter die cavity. A hardened steelpunch was then inserted into the cavity and the material was compressedat 2000 psi for 4-5 minutes using a bench top hydraulic press. The punchis then removed to expose the 0.5 cm² pellet surface. A Viton gasket isthen placed around the threaded shoulder of the die and a polypropylenecap is threaded onto the die. This process can be repeated to generateas many pellets as is necessary for the experiment.

Setup of Intrinsic Dissolution Apparatus:

A Distek Dissolution System equipped with a model number TCS0200Ctemperature control system was filled with water and set to atemperature of 37.3° C. The vessel cavities were then equipped with four1 L flat-bottomed Distek dissolution vessels. Four vessels were thenfilled with 500 mL of the following media: 0.1 N HCl, pH 4.5 acetatebuffer, pH 6.8 phosphate buffer, and USP grade water. The solutions wereallowed to warm in the water bath for approximately 1 hour, but notexceeding 3 hours, or until the temperature of the media matched that ofthe water bath. Paddles were then mounted to the Distek stirringapparatus above the four dissolution vessels such that the distancebetween the paddle and the die face is 1 inch. The paddle speed is thenset to 50 RPM.

Intrinsic Dissolution Dose Dumping Profiles:

Note: The following procedures were derived from the FDA Draft Guidancefor Oxymorphone Hydrochloride (recommended in November, 2007).

Preparation of API Pellet for Intrinsic Dissolution Dose DumpingProfile:

The material which is to be subjected to dissolution is weighed using ananalytical balance. 85.00-95.00 mgs of the analyte was weighed andtransferred to an International Crystals Laboratories fixed/static disk316 stainless die with a 0.8 cm diameter die cavity. A hardened steelpunch was then inserted into the cavity and the material was compressedat 2000 psi for 4-5 minutes using a bench top hydraulic press. The punchis then removed to expose the 0.5 cm² pellet surface. A Viton gasket isthen placed around the threaded shoulder of the die and a polypropylenecap is threaded onto the die. This process can be repeated to generateas many pellets as is necessary for the experiment.

Setup of Intrinsic Dissolution Apparatus for Dose Dumping Profile:

A Distek Dissolution System equipped with a model number TCS0200Ctemperature control system, was filled with water and set to atemperature of 37.3° C. The vessel cavities were then equipped with four1 L flat-bottomed Distek dissolution vessels. The vessels were thenfilled with 900 mL of the following media: 0.1 N HCl, 5% ethanolsolution, 20% ethanol Solution, and 40% ethanol solution. The solutionswere allowed to warm in the water bath for approximately 1 hour, but notexceeding 3 hours, or until the temperature of the media matched that ofthe water bath. Paddles were then mounted to the Distek stirringapparatus above the four dissolution vessels such that the distancebetween the paddle and the die face is 1 inch. The paddle speed is thenset to 75 RPM.

Performing an Intrinsic Dissolution Experiment (Dose Dumping or pHMedia):

The pellet prepared as described above is submerged into a vesselprepared as described above, with the pellet surface facing up (metaldie up, polypropylene cap facing down). Forceps are used to aid thisprocess so that the pellet apparatus can be gently placed into thebottom of the vessel. A timer is used to track the sampling intervals,and is started when the pellet is dropped into the solution. The lid tothe dissolution apparatus is then lowered and the stirring apparatus isactivated. Some planning is required in spacing out pellet drops suchthat each vessel can be sampled at the desired time intervals. Samplingis done by aspirating 10 mL of the solution using a Popper® Micro-Mate®Interchangeable Hypodermic Syringe equipped with a Vortex Pharma Group10 micron cannula porous filter. This filter should be replaced aftereach use. Although sampling intervals can change from experiment toexperiment, the following has been heavily utilized for the experimentsdescribed herein. Sampling occurring at t=0, 5, 10, 15, 30, 45, 60, 90,120, 150, 180 (in minutes).

HPLC Methodology

HPLC Procedure for Analyzing Opioid Pamoates and Xinafoates:

All samples should be analyzed with bracketing standard injections. Thestandard used should be from a qualified vendor with a known purity.Standard solutions should be prepared to have a concentration that isapproximate to that of the samples being analyzed. All samples were ranon a Waters Alliance 2695 Separations Module model number WAT270008equipped with a Alliance 996 Photodiode Array Detector model number186000869. The instrument was equipped with an Agilent 300 Extend-C18 5μm 4.6×250 mm Zorbax column (PN 770995-902). The instrument was thenplumbed with the proper solutions mentioned above in the section titled“Preparation of Solutions”. The instrument is then set to initial columnconditions (see gradient table below):

Time (minutes) % A % B 0.00 90 10 2.00 90 10 8.00 25 75 8.01 0 100 13.000 100 13.01 90 10 17.00 90 10

This method can be used to analyze samples to plot a dissolution profileor to determine the ratio of drug to organic salt. Due to thesignificant difference in response factors between pamoate or xinafoatesalts, a dilution is sometimes required to quantify the salt portion ofthe mixture. Typically a solution prepared at roughly 500 μg/mL needs tobe diluted by a factor of 20 in order to quantify the pamoate moiety,and the corresponding amine should always be quantified using the stocksolution. An exception to this occurs with imipramine pamoate.Imipramine pamoate injections do not require a subsequent dilution whenthe chromatographic data is extracted at 269 nm. All other injectionsshould be extracted at 254 nm, and even imipramine pamoate can beextracted at this wavelength if the solution is diluted properly (seeabove) when quantifying the ratio of amine to pamoate.

The sample diluent utilized also has an impact on the chromatographywhen implementing this method. The following sample diluents were usedwhen analyzing the corresponding pamoate salts for ratio analysis, aswell as dissolution profiles. Also, all ratio determinations and ratioplots are determined based on a known standard as identified in thetable below.

Material Diluent (H₂O:ACN) Racemic-Methylphenidate HCl (standard)  62:38d-Methylphenidate HCl (standard  62:38 Dextroamphetamine Sulfate(standard) 100:0  Racemic-Methylphenidate Pamoate  62:38d-Methylphenidate Pamoate  62:38 Dextroamphetamine Pamoate  62:38Imipramine Pamoate  62:38 Imipramine HCl (standard)  62:38 DisodiumPamoate (standard)  62:38

In some cases when the typical 62:38 diluent is not sufficient to form asolution, a minimal amount of DMSO can be added to dissolve thematerial, and then the flask should be diluted to volume with 62:38(H₂O:ACN).

The present invention has been described with particular reference tothe preferred embodiments without limit thereto. One of skill in the artwould realize additional embodiments, alterations and improvements whichare not specifically set forth but which are within the metes and boundsof the present application as set forth more particularly in the claimsappended hereto.

The invention claimed is:
 1. A drug product not susceptible to dosedumping wherein said drug product comprises a drug substance whereinsaid drug substance is selected from the group consisting of: amorphousracemic-methylphenidate pamoate characterized by at least one methodselected from the group consisting of: an endothermic phase change of atleast 70 J/gram at greater than 200° C.; an FTIR spectrum of FIG. 2; anda PXRD diffractogram of FIG. 3; polymorphic racemic-methylphenidatestearylamine pamoate characterized by at least one method selected fromthe group consisting of: an endothermic phase change of at least 15 J/gat a temperature above 50° C.; an endothermic phase change of at least10 J/g at a temperature of above 90° C.; an endothermic phase change ofat least 2 J/g at a temperature above 105° C.; an endothermic phasechange of at least 4 J/g at above 155° C. and an endothermic phasechange of at least 20 J/g above 180° C.; and a PXRD diffractogram ofFIG. 48; amorphous d-methylphenidate pamoate characterized by at leastone method selected from the group consisting of: an endothermic phasechange of at least 45 J/gram at greater than 70° C. and an endothermicphase change of at least 30 J/gram at greater than 180° C.; an FTIRspectrum of FIG. 11; and a PXRD diffractogram of FIG. 12; amorphousd-methylphenidate xinafoate characterized by at least one methodselected from the group consisting of: an endothermic phase change of atleast 10 J/gram at greater than 45° C. and an endothermic phase changeof at least 50 J/gram at greater than 160° C.; an FTIR spectrum of FIG.17; and a PXRD diffractogram of FIG. 18; polymorphic dextro-amphetaminexinafoate characterized by at least one method selected from the groupconsisting of: an endothermic phase change of at least 60 J/gram atgreater than 125° C.; an FTIR spectrum of FIG. 26; and a PXRDdiffractogram of FIG. 27; polymorphic d-methylphenidate pamoatecharacterized by at least one method selected from the group consistingof: an endothermic phase change of at least 35 J/gram at greater than185° C.; an FTIR spectrum of FIG. 14; and a PXRD diffractogram of FIG.15; polymorphic racemic-methylphenidate pamoate characterized by atleast one method selected from the group consisting of: an endothermicphase change of at least 75 J/gram at greater than 200° C.; an FTIRspectrum of FIG. 5; and a PXRD diffractogram of FIG. 6; polymorphicracemic-methylphenidate xinafoate characterized by at least one methodselected from the group consisting of: an endothermic phase change of atleast 75 J/gram at greater than 155° C.; an FTIR spectrum of FIG. 8; anda PXRD diffractogram of FIG. 9; amorphous dextro-amphetamine pamoatecharacterized by at least one method selected from the group consistingof: endothermic phase change of at least 10 J/gram at greater than 200°C. and an endothermic phase change of at least 75 J/gram at greater than220° C.; an FTIR spectrum of FIG. 20; and a PXRD diffractogram of FIG.21; polymorphic dextro-amphetamine pamoate characterized by at least onemethod selected from the group consisting of: an endothermic phasechange of at least 60 J/gram at greater than 200° C.; an FTIR spectrumof FIG. 23; and a PXRD diffractogram of FIG. 24; amorphousd-methylphenidate mono-triethylammonium pamoate characterized by atleast one method selected from the group consisting of: an endothermicphase change of at least 12 J/g at a temperature above 240° C. an FTIRspectrum of FIG. 51; a PXRD diffractogram of FIG. 52; and ¹H NMRspectrum of FIG. 53; amorphous imipramine mono-triethylammonium pamoatecharacterized by at least one method selected from the group consistingof: an FTIR spectrum of FIG. 59; a PXRD diffractogram of FIG. 60; and ¹HNMR spectrum of FIG. 61; polymorphic imipramine stearylamine pamoatecharacterized by at least one method selected from the group consistingof: an endothermic phase change of at least 40 J/g at a temperatureabove 70° C. and an endothermic phase change of at least 1 J/g above125° C.; an FTIR spectrum of FIG. 63; a PXRD diffractogram of FIG. 64;and ¹H NMR spectrum of FIG. 65; amorphous imipramine,CH₃(O(CH₂)₂)_(x)(OCH₂CHCH₃)_(y)NH₂ wherein Y/X is 9:1 with anapproximate MW of 600, pamoate characterized by at least one methodselected from the group consisting of: an endothermic phase change of atleast 50 J/g at a temperature above 240° C.; an FTIR spectrum of FIG.67; a PXRD diffractogram of FIG. 68; and ¹H NMR spectrum of FIG. 69;amorphous hydrocodone stearylamine pamoate characterized by at least onemethod selected from the group consisting of: an endothermic phasechange of at least 1 J/g at a temperature above 65° C.; an endothermicphase change of at least 1 J/g above 70° C. and an endothermic phasechange of at least 3 J/g above 105° C.; an FTIR spectrum of FIG. 71; aPXRD diffractogram of FIG. 72; and ¹H NMR spectrum of FIG. 73; amorphoushydrocodone, CH₃(O(CH₂)₂)_(x)(OCH₂CHCH₃)_(y)NH₂ wherein Y/X is 9:1 withan approximate MW of 600, pamoate characterized by at least one methodselected from the group consisting of: an endothermic phase change of atleast 5 J/g at a temperature above 105° C. and an endothermic phasechange of at least 1 J/g at a temperature above 150° C.; an FTIRspectrum of FIG. 75; a PXRD diffractogram of FIG. 76; and ¹H NMRspectrum of FIG. 77; polymorphic imipramine pamoate (1:1) characterizedby at least one method selected from the group consisting of: anendothermic phase change of at least 60 J/g at a temperature above 200°C.; an FTIR spectrum of FIG. 105; a PXRD diffractogram of FIG. 106; and¹H NMR spectrum of FIG. 107; and amorphous imipramine pamoate (1:1)characterized by at least one method selected from the group consistingof: a DSC spectrum of FIG. 54; an FTIR spectrum of FIG. 55; a PXRDdiffractogram of FIG. 56; and ¹H NMR spectrum of FIG. 57; and said drugsubstance meets at least one condition in 0.1 N HCl selected from thegroup consisting of: no more than 35% of said drug substance is releasedat 30 minutes with 5 wt % ethanol in said 0.1 N HCl; the percentage ofsaid drug substance released with at least 5 wt % ethanol in said 0.1 NHCl is no more than a percentage of said drug substance released in said0.1 N HCl without ethanol; and the percentage of drug substance releasedwith 40 wt % ethanol in 0.1 N HCl does not exceed 60% while thepercentage of drug substance released under the conditions selected fromwater, 0.1 N HCl, 5 wt % ethanol in 0.1 N HCl and 20 wt % ethanol in 0.1N HCl does not exceed the drug substance released with 40 wt % ethanolin 0.1 N HCl.
 2. The drug product not susceptible to dose dumping ofclaim 1 wherein no more than 35% of said drug substance is released at45 minutes with 5 wt % ethanol in said 0.1 N HCl.
 3. A drug product notsusceptible to dose dumping wherein said drug product comprises a drugsubstance wherein said drug substance is a pharmaceutically acceptableorganic acid salt of an amine containing pharmaceutically activecompound selected from the group consisting of amphetamine,methylphenidate, imipramine and hydrocodone and said drug substancemeets at least one condition in 0.1 N HCl selected from the groupconsisting of: no more than 35% of said drug substance is released at 30minutes with 5 wt % ethanol in said 0.1 N HCl; the percentage of saiddrug substance released with at least 5 wt % ethanol in said 0.1 N HClis no more than a percentage of said drug substance released in said 0.1N HCl without ethanol; and the percentage of drug substance releasedwith 40 wt % ethanol in 0.1 N HCl does not exceed 60% while thepercentage of drug substance released under the conditions selected fromwater, 0.1 N HCl, 5 wt % ethanol in 0.1 N HCl and 20 wt % ethanol in 0.1N HCl does not exceed the drug substance released with 40 wt % ethanolin 0.1 N HCl wherein said drug substance is amorphousracemic-methylphenidate pamoate has an endothermic phase change of atleast 70 J/gram at greater than 200° C.
 4. A drug product notsusceptible to dose dumping wherein said drug product comprises a drugsubstance wherein said drug substance is a pharmaceutically acceptableorganic acid salt of an amine containing pharmaceutically activecompound selected from the group consisting of amphetamine,methylphenidate, imipramine and hydrocodone and said drug substancemeets at least one condition in 0.1 N HCl selected from the groupconsisting of: no more than 35% of said drug substance is released at 30minutes with 5 wt % ethanol in said 0.1 N HCl; the percentage of saiddrug substance released with at least 5 wt % ethanol in said 0.1 N HClis no more than a percentage of said drug substance released in said 0.1N HCl without ethanol; and the percentage of drug substance releasedwith 40 wt % ethanol in 0.1 N HCl does not exceed 60% while thepercentage of drug substance released under the conditions selected fromwater, 0.1 N HCl, 5 wt % ethanol in 0.1 N HCl and 20 wt % ethanol in 0.1N HCl does not exceed the drug substance released with 40 wt % ethanolin 0.1 N HCl wherein said drug substance is amorphousracemic-methylphenidate pamoate has an FTIR spectrum of FIG.
 2. 5. Adrug product not susceptible to dose dumping wherein said drug productcomprises a drug substance wherein said drug substance is apharmaceutically acceptable organic acid salt of an amine containingpharmaceutically active compound selected from the group consisting ofamphetamine, methylphenidate, imipramine and hydrocodone and said drugsubstance meets at least one condition in 0.1 N HCl selected from thegroup consisting of: no more than 35% of said drug substance is releasedat 30 minutes with 5 wt % ethanol in said 0.1 N HCl; the percentage ofsaid drug substance released with at least 5 wt % ethanol in said 0.1 NHCl is no more than a percentage of said drug substance released in said0.1 N HCl without ethanol; and the percentage of drug substance releasedwith 40 wt % ethanol in 0.1 N HCl does not exceed 60% while thepercentage of drug substance released under the conditions selected fromwater, 0.1 N HCl, 5 wt % ethanol in 0.1 N HCl and 20 wt % ethanol in 0.1N HCl does not exceed the drug substance released with 40 wt % ethanolin 0.1 N HCl wherein said drug substance is amorphousracemic-methylphenidate pamoate has a PXRD diffractogram of FIG.
 3. 6. Adrug product not susceptible to dose dumping wherein said drug productcomprises a drug substance wherein said drug substance is selected fromthe group consisting of: amorphous racemic-methylphenidate pamoatecharacterized by at least one method selected from the group consistingof: an endothermic phase change of at least 70 J/gram at greater than200° C.; an FTIR spectrum of FIG. 2; and a PXRD diffractogram of FIG. 3;polymorphic racemic-methylphenidate stearylamine pamoate characterizedby at least one method selected from the group consisting of: anendothermic phase change of at least 15 J/g at a temperature above 50°C.; an endothermic phase change of at least 10 J/g at a temperature ofabove 90° C.; an endothermic phase change of at least 2 J/g at atemperature above 105° C.; an endothermic phase change of at least 4 J/gat above 155° C. and an endothermic phase change of at least 20 J/gabove 180° C.; and a PXRD diffractogram of FIG. 48; amorphousd-methylphenidate pamoate characterized by at least one method selectedfrom the group consisting of: an endothermic phase change of at least 45J/gram at greater than 70° C. and an endothermic phase change of atleast 30 J/gram at greater than 180° C.; an FTIR spectrum of FIG. 11;and a PXRD diffractogram of FIG. 12; amorphous d-methylphenidatexinafoate characterized by at least one method selected from the groupconsisting of: an endothermic phase change of at least 10 J/gram atgreater than 45° C. and an endothermic phase change of at least 50J/gram at greater than 160° C.; an FTIR spectrum of FIG. 17; and a PXRDdiffractogram of FIG. 18; polymorphic dextro-amphetamine xinafoatecharacterized by at least one method selected from the group consistingof: an endothermic phase change of at least 60 J/gram at greater than125° C.; an FTIR spectrum of FIG. 26; and a PXRD diffractogram of FIG.27; polymorphic d-methylphenidate pamoate characterized by at least onemethod selected from the group consisting of: an endothermic phasechange of at least 35 J/gram at greater than 185° C.; an FTIR spectrumof FIG. 14; and a PXRD diffractogram of FIG. 15; polymorphicracemic-methylphenidate pamoate characterized by at least one methodselected from the group consisting of: an endothermic phase change of atleast 75 J/gram at greater than 200° C.; an FTIR spectrum of FIG. 5; anda PXRD diffractogram of FIG. 6; polymorphic racemic-methylphenidatexinafoate characterized by at least one method selected from the groupconsisting of: an endothermic phase change of at least 75 J/gram atgreater than 155° C.; an FTIR spectrum of FIG. 8; and a PXRDdiffractogram of FIG. 9; amorphous dextro-amphetamine pamoatecharacterized by at least one method selected from the group consistingof: endothermic phase change of at least 10 J/gram at greater than 200°C. and an endothermic phase change of at least 75 J/gram at greater than220° C.; an FTIR spectrum of FIG. 20; and a PXRD diffractogram of FIG.21; polymorphic dextro-amphetamine pamoate characterized by at least onemethod selected from the group consisting of: an endothermic phasechange of at least 60 J/gram at greater than 200° C.; an FTIR spectrumof FIG. 23; and a PXRD diffractogram of FIG. 24; and amorphousd-methylphenidate mono-triethylammonium pamoate characterized by atleast one method selected from the group consisting of: an endothermicphase change of at least 12 J/g at a temperature above 240° C. an FTIRspectrum of FIG. 51; a PXRD diffractogram of FIG. 52; and ¹H NMRspectrum of FIG. 53; and said drug substance meets at least onecondition in 0.1 N HCl selected from the group consisting of: no morethan 35% of said drug substance is released at 30 minutes with 5 wt %ethanol in said 0.1 N HCl; the percentage of said drug substancereleased with at least 5 wt % ethanol in said 0.1 N HCl is no more thana percentage of said drug substance released in said 0.1 N HCl withoutethanol; and the percentage of drug substance released with 40 wt %ethanol in 0.1 N HCl does not exceed 60% while the percentage of drugsubstance released under the conditions selected from water, 0.1 N HCl,5 wt % ethanol in 0.1 N HCl and 20 wt % ethanol in 0.1 N HCl does notexceed the drug substance released with 40 wt % ethanol in 0.1 N HCl. 7.The drug product not susceptible to dose dumping of claim 6 wherein drugsubstance is selected from the group consisting of: polymorphicdextro-amphetamine xinafoate characterized by at least one methodselected from the group consisting of: an endothermic phase change of atleast 60 J/gram at greater than 125° C.; an FTIR spectrum of FIG. 26;and a PXRD diffractogram of FIG. 27; amorphous dextro-amphetaminepamoate characterized by at least one method selected from the groupconsisting of: endothermic phase change of at least 10 J/gram at greaterthan 200° C. and an endothermic phase change of at least 75 J/gram atgreater than 220° C.; an FTIR spectrum of FIG. 20; and a PXRDdiffractogram of FIG. 21; and polymorphic dextro-amphetamine pamoatecharacterized by at least one method selected from the group consistingof: an endothermic phase change of at least 60 J/gram at greater than200° C.; an FTIR spectrum of FIG. 23; and a PXRD diffractogram of FIG.24; and said drug substance meets at least one condition in 0.1 N HClselected from the group consisting of: no more than 35% of said drugsubstance is released at 30 minutes with 5 wt % ethanol in said 0.1 NHCl; the percentage of said drug substance released with at least 5 wt %ethanol in said 0.1 N HCl is no more than a percentage of said drugsubstance released in said 0.1 N HCl without ethanol; and the percentageof drug substance released with 40 wt % ethanol in 0.1 N HCl does notexceed 60% while the percentage of drug substance released under theconditions selected from water, 0.1 N HCl, 5 wt % ethanol in 0.1 N HCland 20 wt % ethanol in 0.1 N HCl does not exceed the drug substancereleased with 40 wt % ethanol in 0.1 N HCl.
 8. The drug product notsusceptible to dose dumping of claim 6 wherein said drug substance isselected from the group consisting of: amorphous racemic-methylphenidatepamoate characterized by at least one method selected from the groupconsisting of: an endothermic phase change of at least 70 J/gram atgreater than 200° C.; an FTIR spectrum of FIG. 2; and a PXRDdiffractogram of FIG. 3; polymorphic racemic-methylphenidatestearylamine pamoate characterized by at least one method selected fromthe group consisting of: an endothermic phase change of at least 15 J/gat a temperature above 50° C.; an endothermic phase change of at least10 J/g at a temperature of above 90° C.; an endothermic phase change ofat least 2 J/g at a temperature above 105° C.; an endothermic phasechange of at least 4 J/g at above 155° C. and an endothermic phasechange of at least 20 J/g above 180° C.; and a PXRD diffractogram ofFIG. 48; amorphous d-methylphenidate pamoate characterized by at leastone method selected from the group consisting of: an endothermic phasechange of at least 45 J/gram at greater than 70° C. and an endothermicphase change of at least 30 J/gram at greater than 180° C.; an FTIRspectrum of FIG. 11; and a PXRD diffractogram of FIG. 12; amorphousd-methylphenidate xinafoate characterized by at least one methodselected from the group consisting of: an endothermic phase change of atleast 10 J/gram at greater than 45° C. and an endothermic phase changeof at least 50 J/gram at greater than 160° C.; an FTIR spectrum of FIG.17; and a PXRD diffractogram of FIG. 18; polymorphic d-methylphenidatepamoate characterized by at least one method selected from the groupconsisting of: an endothermic phase change of at least 35 J/gram atgreater than 185° C.; an FTIR spectrum of FIG. 14; and a PXRDdiffractogram of FIG. 15; polymorphic racemic-methylphenidate pamoatecharacterized by at least one method selected from the group consistingof: an endothermic phase change of at least 75 J/gram at greater than200° C.; an FTIR spectrum of FIG. 5; and a PXRD diffractogram of FIG. 6;polymorphic racemic-methylphenidate xinafoate characterized by at leastone method selected from the group consisting of: an endothermic phasechange of at least 75 J/gram at greater than 155° C.; an FTIR spectrumof FIG. 8; and a PXRD diffractogram of FIG. 9; and amorphousd-methylphenidate mono-triethylammonium pamoate characterized by atleast one method selected from the group consisting of: an endothermicphase change of at least 12 J/g at a temperature above 240° C. an FTIRspectrum of FIG. 51; a PXRD diffractogram of FIG. 52; and ¹H NMRspectrum of FIG. 53; and said drug substance meets at least onecondition in 0.1 N HCl selected from the group consisting of: no morethan 35% of said drug substance is released at 30 minutes with 5 wt %ethanol in said 0.1 N HCl; the percentage of said drug substancereleased with at least 5 wt % ethanol in said 0.1 N HCl is no more thana percentage of said drug substance released in said 0.1 N HCl withoutethanol; and the percentage of drug substance released with 40 wt %ethanol in 0.1 N HCl does not exceed 60% while the percentage of drugsubstance released under the conditions selected from water, 0.1 N HCl,5 wt % ethanol in 0.1 N HCl and 20 wt % ethanol in 0.1 N HCl does notexceed the drug substance released with 40 wt % ethanol in 0.1 N HCl. 9.The drug product not susceptible to dose dumping of claim 1 wherein saidsubstance is selected from the group consisting of: amorphous imipraminemono-triethylammonium pamoate characterized by at least one methodselected from the group consisting of: an FTIR spectrum of FIG. 59; aPXRD diffractogram of FIG. 60; and ¹H NMR spectrum of FIG. 61;polymorphic imipramine stearylamine pamoate characterized by at leastone method selected from the group consisting of: an endothermic phasechange of at least 40 J/g at a temperature above 70° C. and anendothermic phase change of at least 1 J/g above 125° C.; an FTIRspectrum of FIG. 63; a PXRD diffractogram of FIG. 64; and ¹H NMRspectrum of FIG. 65; amorphous imipramine,CH₃(O(CH₂)₂)_(x)(OCH₂CHCH₃)_(y)NH₂ wherein Y/X is 9:1 with anapproximate MW of 600, pamoate characterized by at least one methodselected from the group consisting of: an endothermic phase change of atleast 50 J/g at a temperature above 240° C.; an FTIR spectrum of FIG.67; a PXRD diffractogram of FIG. 68; and ¹H NMR spectrum of FIG. 69;amorphous hydrocodone stearylamine pamoate characterized by at least onemethod selected from the group consisting of: an endothermic phasechange of at least 1 J/g at a temperature above 65° C.; an endothermicphase change of at least 1 J/g above 70° C. and an endothermic phasechange of at least 3 J/g above 105° C.; an FTIR spectrum of FIG. 71; aPXRD diffractogram of FIG. 72; and ¹H NMR spectrum of FIG. 73; amorphoushydrocodone, CH₃(O(CH₂)₂)_(x)(OCH₂CHCH₃)_(y)NH₂ wherein Y/X is 9:1 withan approximate MW of 600, pamoate characterized by at least one methodselected from the group consisting of: an endothermic phase change of atleast 5 J/g at a temperature above 105° C. and an endothermic phasechange of at least 1 J/g at a temperature above 150° C.; an FTIRspectrum of FIG. 75; a PXRD diffractogram of FIG. 76; and ¹H NMRspectrum of FIG. 77; polymorphic imipramine pamoate (1:1) characterizedby at least one method selected from the group consisting of: anendothermic phase change of at least 60 J/g at a temperature above 200°C.; an FTIR spectrum of FIG. 105; a PXRD diffractogram of FIG. 106; and¹H NMR spectrum of FIG. 107; and amorphous imipramine pamoate (1:1)characterized by at least one method selected from the group consistingof: a DSC spectrum of FIG. 54; an FTIR spectrum of FIG. 55; a PXRDdiffractogram of FIG. 56; and ¹H NMR spectrum of FIG. 57; and said drugsubstance meets at least one condition in 0.1 N HCl selected from thegroup consisting of: no more than 35% of said drug substance is releasedat 30 minutes with 5 wt % ethanol in said 0.1 N HCl; the percentage ofsaid drug substance released with at least 5 wt % ethanol in said 0.1 NHCl is no more than a percentage of said drug substance released in said0.1 N HCl without ethanol; and the percentage of drug substance releasedwith 40 wt % ethanol in 0.1 N HCl does not exceed 60% while thepercentage of drug substance released under the conditions selected fromwater, 0.1 N HCl, 5 wt % ethanol in 0.1 N HCl and 20 wt % ethanol in 0.1N HCl does not exceed the drug substance released with 40 wt % ethanolin 0.1 N HCl.